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CalcDalton: a tool for multiplex genotyping primer design for single-base extension reactions using cleavable primers
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Holger Kirsten, Steffen Dienst, Frank Emmrich, Peter Ahnert

Date Published: 2006

Publication Type: Journal article

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline …e PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 \times 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 \times 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 \times 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 \times 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 \times 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

Authors: Xin Yang, Goska Leslie, Alicja Doroszuk, Sandra Schneider, Jamie Allen, Brennan Decker, Alison M. Dunning, James Redman, James Scarth, Inga Plaskocinska, Craig Luccarini, Mitul Shah, Karen Pooley, Leila Dorling, Andrew Lee, Muriel A. Adank, Julian Adlard, Kristiina Aittomäki, Irene L. Andrulis, Peter Ang, Julian Barwell, Jonine L. Bernstein, Kristie Bobolis, Åke Borg, Carl Blomqvist, Kathleen B. M. Claes, Patrick Concannon, Adeline Cuggia, Julie O. Culver, Francesca Damiola, Antoine de Pauw, Orland Diez, Jill S. Dolinsky, Susan M. Domchek, Christoph Engel, D. Gareth Evans, Florentia Fostira, Judy Garber, Lisa Golmard, Ellen L. Goode, Stephen B. Gruber, Eric Hahnen, Christopher Hake, Tuomas Heikkinen, Judith E. Hurley, Ramunas Janavicius, Zdenek Kleibl, Petra Kleiblova, Irene Konstantopoulou, Anders Kvist, Holly Laduca, Ann S. G. Lee, Fabienne Lesueur, Eamonn R. Maher, Arto Mannermaa, Siranoush Manoukian, Rachel McFarland, Wendy McKinnon, Alfons Meindl, Kelly Metcalfe, Nur Aishah Mohd Taib, Jukka Moilanen, Katherine L. Nathanson, Susan Neuhausen, Pei Sze Ng, Tu Nguyen-Dumont, Sarah M. Nielsen, Florian Obermair, Kenneth Offit, Olufunmilayo I. Olopade, Laura Ottini, Judith Penkert, Katri Pylkäs, Paolo Radice, Susan J. Ramus, Vilius Rudaitis, Lucy Side, Rachel Silva-Smith, Valentina Silvestri, Anne-Bine Skytte, Thomas Slavin, Jana Soukupova, Carlo Tondini, Alison H. Trainer, Gary Unzeitig, Lydia Usha, Thomas van Overeem Hansen, James Whitworth, Marie Wood, Cheng Har Yip, Sook-Yee Yoon, Amal Yussuf, George Zogopoulos, David Goldgar, John L. Hopper, Georgia Chenevix-Trench, Paul Pharoah, Sophia H. L. George, Judith Balmaña, Claude Houdayer, Paul James, Zaki El-Haffaf, Hans Ehrencrona, Marketa Janatova, Paolo Peterlongo, Heli Nevanlinna, Rita Schmutzler, Soo-Hwang Teo, Mark Robson, Tuya Pal, Fergus Couch, Jeffrey N. Weitzel, Aaron Elliott, Melissa Southey, Robert Winqvist, Douglas F. Easton, William D. Foulkes, Antonis C. Antoniou, Marc Tischkowitz

Date Published: 1st Mar 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers …s of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. METHODS Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. RESULTS The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. CONCLUSION There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. IMPACT Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

Authors: Paolo Peterlongo, Jenny Chang-Claude, Kirsten B. Moysich, Anja Rudolph, Rita K. Schmutzler, Jacques Simard, Penny Soucy, Rosalind A. Eeles, Douglas F. Easton, Ute Hamann, Stefan Wilkening, Bowang Chen, Matti A. Rookus, Marjanka K. Schmidt, Frederieke H. van der Baan, Amanda B. Spurdle, Logan C. Walker, Felicity Lose, Ana-Teresa Maia, Marco Montagna, Laura Matricardi, Jan Lubinski, Anna Jakubowska, Encarna B. Gómez Garcia, Olufunmilayo I. Olopade, Robert L. Nussbaum, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Banu K. Arun, Beth Y. Karlan, Sandra Orsulic, Jenny Lester, Wendy K. Chung, Alex Miron, Melissa C. Southey, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Yuan Chun Ding, Susan L. Neuhausen, Thomas v. O. Hansen, Anne-Marie Gerdes, Bent Ejlertsen, Lars Jønson, Ana Osorio, Cristina Martínez-Bouzas, Javier Benitez, Edye E. Conway, Kathleen R. Blazer, Jeffrey N. Weitzel, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Monica Barile, Filomena Ficarazzi, Frederique Mariette, Stefano Fortuzzi, Alessandra Viel, Giuseppe Giannini, Laura Papi, Aline Martayan, Maria Grazia Tibiletti, Paolo Radice, Athanassios Vratimos, Florentia Fostira, Judy E. Garber, Alan Donaldson, Carole Brewer, Claire Foo, D. Gareth R. Evans, Debra Frost, Diana Eccles, Angela Brady, Jackie Cook, Marc Tischkowitz, Julian Adlard, Julian Barwell, Lisa Walker, Louise Izatt, Lucy E. Side, M. John Kennedy, Mark T. Rogers, Mary E. Porteous, Patrick J. Morrison, Radka Platte, Rosemarie Davidson, Shirley V. Hodgson, Steve Ellis, Trevor Cole, Andrew K. Godwin, Kathleen Claes, Tom van Maerken, Alfons Meindl, Andrea Gehrig, Christian Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Hansjoerg Plendl, Karin Kast, Kerstin Rhiem, Nina Ditsch, Norbert Arnold, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Shan Wang-Gohrke, Brigitte Bressac-de Paillerets, Bruno Buecher, Capucine Delnatte, Claude Houdayer, Dominique Stoppa-Lyonnet, Francesca Damiola, Isabelle Coupier, Laure Barjhoux, Laurence Venat-Bouvet, Lisa Golmard, Nadia Boutry-Kryza, Olga M. Sinilnikova, Olivier Caron, Pascal Pujol, Sylvie Mazoyer, Muriel Belotti, Marion Piedmonte, Michael L. Friedlander, Gustavo C. Rodriguez, Larry J. Copeland, Miguel de La Hoya, Pedro Perez Segura, Heli Nevanlinna, Kristiina Aittomäki, Theo A. M. van Os, Hanne E. J. Meijers-Heijboer, Annemarie H. van der Hout, Maaike P. G. Vreeswijk, Nicoline Hoogerbrugge, Margreet G. E. M. Ausems, Helena C. van Doorn, J. Margriet Collée, Edith Olah, Orland Diez, Ignacio Blanco, Conxi Lazaro, Joan Brunet, Lidia Feliubadalo, Cezary Cybulski, Jacek Gronwald, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Grzegorz Sukiennicki, Adalgeir Arason, Jocelyne Chiquette, Manuel R. Teixeira, Curtis Olswold, Fergus J. Couch, Noralane M. Lindor, Xianshu Wang, Csilla I. Szabo, Kenneth Offit, Marina Corines, Lauren Jacobs, Mark E. Robson, Liying Zhang, Vijai Joseph, Andreas Berger, Christian F. Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng M. Tea, Catherine M. Phelan, Mark H. Greene, Phuong L. Mai, Gad Rennert, Anna Marie Mulligan, Gord Glendon, Sandrine Tchatchou, Irene L. Andrulis, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Mads Thomassen, Uffe Birk Jensen, Yael Laitman, Johanna Rantala, Anna von Wachenfeldt, Hans Ehrencrona, Marie Stenmark Askmalm, Åke Borg, Karoline B. Kuchenbaecker, Lesley McGuffog, Daniel Barrowdale, Sue Healey, Andrew Lee, Paul D. P. Pharoah, Georgia Chenevix-Trench, Antonis C. Antoniou, Eitan Friedman

Date Published: 13th Jan 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Cardiac surgery fast-track treatment in a postanesthetic care unit: six-month results of the Leipzig fast-track concept
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe authors compared the safety and efficacy of a newly developed fast-track concept at their center, including implementation of a direct admission postanesthetic care … unit, to standard perioperative management.\backslashr\backslashnMETHODS\backslashr\backslashnAll fast-track patients treated within the first 6 months of implementation of our direct admission postanesthetic care unit were matched via propensity scores and compared with a historical control group of patients who underwent cardiac surgery prior to fast-track implementation.\backslashr\backslashnRESULTS\backslashr\backslashnA total of 421 fast-track patients were matched successfully to 421 control patients. The two groups of patients had a similar age (64 +/- 13 vs. 64 +/- 12 yr for fast-track vs. control, P = 0.45) and European System for Cardiac Operative Risk Evaluation-predicted risk of mortality (4.8 +/- 6.1% vs. 4.6 +/- 5.1%, P = 0.97). Fast-track patients had significantly shorter times to extubation (75 min [45-110] vs. 900 min [600-1140]), as well as shorter lengths of stay in the postanesthetic or intensive care unit (4 h [3.0-5] vs. 20 h [16-25]), intermediate care unit (21 h [17-39] vs. 26 h [19-49]), and hospital (10 days [8-12] vs. 11 days [9-14]) (expressed as median and interquartile range, all P \textless 0.01). Fast-track patients also had a lower risk of postoperative low cardiac output syndrome (0.5% vs. 2.9%, P \textless 0.05) and mortality (0.5% vs. 3.3%, P \textless 0.01).\backslashr\backslashnCONCLUSION\backslashr\backslashnThe Leipzig fast-track protocol is a safe and effective method to manage cardiac surgery patients after a variety of operations. BACKGROUND The authors compared the safety and efficacy of a newly developed fast-track concept at their center, including implementation of a direct admission postanesthetic care unit, to standard perioperative management. METHODS All fast-track patients treated within the first 6 months of implementation of our direct admission postanesthetic care unit were matched via propensity scores and compared with a historical control group of patients who underwent cardiac surgery prior to fast-track implementation. RESULTS A total of 421 fast-track patients were matched successfully to 421 control patients. The two groups of patients had a similar age (64 +/- 13 vs. 64 +/- 12 yr for fast-track vs. control, P = 0.45) and European System for Cardiac Operative Risk Evaluation-predicted risk of mortality (4.8 +/- 6.1% vs. 4.6 +/- 5.1%, P = 0.97). Fast-track patients had significantly shorter times to extubation (75 min [45-110] vs. 900 min [600-1140]), as well as shorter lengths of stay in the postanesthetic or intensive care unit (4 h [3.0-5] vs. 20 h [16-25]), intermediate care unit (21 h [17-39] vs. 26 h [19-49]), and hospital (10 days [8-12] vs. 11 days [9-14]) (expressed as median and interquartile range, all P \textless 0.01). Fast-track patients also had a lower risk of postoperative low cardiac output syndrome (0.5% vs. 2.9%, P \textless 0.05) and mortality (0.5% vs. 3.3%, P \textless 0.01). CONCLUSION The Leipzig fast-track protocol is a safe and effective method to manage cardiac surgery patients after a variety of operations.

Authors: Joerg Ender, Michael Andrew Borger, Markus Scholz, Anne-Kathrin Funkat, Nadeem Anwar, Marcus Sommer, Friedrich Wilhelm Mohr, Jens Fassl

Date Published: 2008

Publication Type: Journal article

Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases.
LHA - Leipzig Health Atlas

Abstract (Expand)

Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective … treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed so far. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent.

Authors: A. Arakelyan, L. Nersisyan, M. Petrek, H. Loffler-Wirth, H. Binder

Date Published: 21st May 2016

Publication Type: Not specified

Human Diseases: lung disease

Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129
Genetical Statistics and Systems Biology

Abstract (Expand)

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, … which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).

Authors: Clarissa Pedrosa da C. Gomes, Bence Ágg, Andrejaana Andova, Serdal Arslan, Andrew Baker, Monika Barteková, Dimitris Beis, Fay Betsou, Stephanie Bezzina Wettinger, Branko Bugarski, Gianluigi Condorelli, Gustavo José Justo da Silva, Sabrina Danilin, David de Gonzalo-Calvo, Alfonso Buil, Maria Carmo-Fonseca, Francisco J. Enguita, Kyriacos Felekkis, Peter Ferdinandy, Mariann Gyöngyösi, Matthias Hackl, Kanita Karaduzovic-Hadziabdic, Jan Hellemans, Stephane Heymans, Markéta Hlavackova, Morten Andre Hoydal, Aleksandra Jankovic, Amela Jusic, Dimitris Kardassis, Risto Kerkelä, Gabriela M. Kuster, Päivi Lakkisto, Przemyslaw Leszek, Mitja Lustrek, Lars Maegdefessel, Fabio Martelli, Susana Novella, Timothy O’Brien, Christos Papaneophytou, Thierry Pedrazzini, Florence Pinet, Octavian Popescu, Ines Potočnjak, Emma Robinson, Shlomo Sasson, Markus Scholz, Maya Simionescu, Monika Stoll, Zoltan V. Varga, Manlio Vinciguerra, Angela Xuereb, Mehmet Birhan Yilmaz, Costanza Emanueli, Yvan Devaux, behalf of the EU-CardioRNA COST Action on

Date Published: 1st Jun 2019

Publication Type: Journal article

Cell cycle, oncogenic and tumor suppressor pathways regulate numerous long and macro non-protein-coding RNAs
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe genome is pervasively transcribed but most transcripts do not code for proteins, constituting non-protein coding RNAs. Despite increasing numbers of functional reports … of individual long noncoding RNAs (lncRNAs), assessing the extent of functionality among the non-coding transcriptional output of mammalian cells remains intricate. In the protein coding world, transcripts differentially expressed in the context of processes essential for the survival of multicellular organisms have been instrumental for the discovery of functionally relevant proteins and their deregulation is frequently associated with diseases. We therefore systematically identify lncRNAs expressed differentially in response to oncologically relevant processes, cell-cycle, p53-, and STAT3 pathway, using tiling arrays.\backslashr\backslashnRESULTS\backslashr\backslashnWe find that up to 80% of the pathway-triggered transcriptional response can be non-coding. Among these we identify very large macroRNAs with pathway-specific expression patterns and demonstrate that these are likely continuous transcripts. MacroRNAs contain elements conserved in mammals and sauropsids, which in part exhibit conserved RNA secondary structure. Comparing evolutionary rates of a macroRNA to adjacent protein coding genes suggests a local action of the transcript. Finally, in different grades of astrocytoma, a tumor disease unrelated to the initially used cell lines, macroRNAs are differentially expressed.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnIt has been shown previously that the majority of expressed non-ribosomal transcripts are non-coding. We now conclude that differential expression triggered by signaling pathways gives rise to a similar abundance of non-coding content. It is thus unlikely that the prevalence of non-coding transcripts in the cell is a trivial consequence of leaky or random transcription events. BACKGROUND The genome is pervasively transcribed but most transcripts do not code for proteins, constituting non-protein-coding RNAs. Despite increasing numbers of functional reports of individual long non-coding RNAs (lncRNAs), assessing the extent of functionality among the non-coding transcriptional output of mammalian cells remains intricate. In the protein-coding world, transcripts differentially expressed in the context of processes essential for the survival of multicellular organisms have been instrumental in the discovery of functionally relevant proteins and their deregulation is frequently associated with diseases. We therefore systematically identified lncRNAs expressed differentially in response to oncologically relevant processes and cell-cycle, p53 and STAT3 pathways, using tiling arrays. RESULTS We found that up to 80% of the pathway-triggered transcriptional responses are non-coding. Among these we identified very large macroRNAs with pathway-specific expression patterns and demonstrated that these are likely continuous transcripts. MacroRNAs contain elements conserved in mammals and sauropsids, which in part exhibit conserved RNA secondary structure. Comparing evolutionary rates of a macroRNA to adjacent protein-coding genes suggests a local action of the transcript. Finally, in different grades of astrocytoma, a tumor disease unrelated to the initially used cell lines, macroRNAs are differentially expressed. CONCLUSIONS It has been shown previously that the majority of expressed non-ribosomal transcripts are non-coding. We now conclude that differential expression triggered by signaling pathways gives rise to a similar abundance of non-coding content. It is thus unlikely that the prevalence of non-coding transcripts in the cell is a trivial consequence of leaky or random transcription events.

Authors: Jörg Hackermüller, Kristin Reiche, Christian Otto, Nadine Hösler, Conny Blumert, Katja Brocke-Heidrich, Levin Böhlig, Anne Nitsche, Katharina Kasack, Peter Ahnert, Wolfgang Krupp, Kurt Engeland, Peter F. Stadler, Friedemann Horn

Date Published: 2014

Publication Type: Journal article

Cellular Adhesion Gene SELP Is Associated with Rheumatoid Arthritis and Displays Differential Allelic Expression // Cellular adhesion gene SELP is associated with rheumatoid arthritis and displays differential allelic expression
Genetical Statistics and Systems Biology

Abstract (Expand)

In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single … nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p\textless10-6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1 = 0.004; p2 = 0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA. In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p\textless10-6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1 = 0.004; p2 = 0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA.

Authors: Jana Burkhardt, Mechthild Blume, Elisabeth Petit-Teixeira, Vitor Hugo Teixeira, Anke Steiner, Elfi Quente, Grit Wolfram, Markus Scholz, Céline Pierlot, Paola Migliorini, Stefano Bombardieri, Alejandro Balsa, René Westhovens, Pilar Barrera, Timothy R D J Radstake, Helena Alves, Thomas Bardin, Bernard Prum, Frank Emmrich, François Cornelis, Peter Ahnert, Holger Kirsten

Date Published: 22nd Aug 2014

Publication Type: Journal article

Central neurocytoma: SNP array analyses, subtel FISH, and review of the literature
Genetical Statistics and Systems Biology

Abstract (Expand)

The central neurocytoma (CN) is a rare brain tumor with a frequency of 0.1-0.5% of all brain tumors. According to the World Health Organization classification, it is a benign grade II tumor with good … prognosis. However, some CN occur as histologically \textquotedblatypical\textquotedbl variant, combined with increasing proliferation and poor clinical outcome. Detailed genetic knowledge could be helpful to characterize a potential atypical behavior in CN. Only few publications on genetics of CN exist in the literature. Therefore, we performed cytogenetic analysis of an intraventricular neurocytoma WHO grade II in a 39-year-old male patient by use of genome-wide high-density single nucleotide polymorphism array (SNP array) and subtelomere FISH. Applying these techniques, we could detect known chromosomal aberrations and identified six not previously described chromosomal aberrations, gains of 1p36.33-p36.31, 2q37.1-q37.3, 6q27, 12p13.33-p13.31, 20q13.31-q13.33, and loss of 19p13.3-p12. Our case report contributes to the genetic knowledge about CN and to increased understanding of \textquotedbltypical\textquotedbl and \textquotedblatypical\textquotedbl variants.

Authors: Caroline Sander, Marco Wallenborn, Vivian Pascal Brandt, Peter Ahnert, Vera Reuschel, Christan Eisenlöffel, Wolfgang Krupp, Jürgen Meixensberger, Heidrun Holland

Date Published: 1st Jul 2019

Publication Type: Journal article

Challenges and experiences extending the cBioPortal for cancer genomics to a molecular tumor board platform
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

In Molecular Tumor Boards (MTBs), therapy recommendations for cancer patients are discussed. To aid decision-making based on the patient’s molecular profile, the research platform cBioPortal was extended … based on users’ requirements. Additionally, a comprehensive dockerized workflow was developed to support the deployment of cBioPortal and connected services. In this work, we present the challenges and experiences of nearly two years of implementing and deploying an MTB platform based on cBioPortal and compare those to findings of a previous study.

Authors: Niklas Reimer, Philipp Unberath, Hauke Busch, Melanie Börries, Patrick Metzger, Arsenij Ustjanzew, Christopher Renner, Hans-Ulrich Prokosch, Jan Christoph

Date Published: 1st Nov 2021

Publication Type: InCollection

Characterization of genomic imbalances in diffuse large B-cell lymphoma by detailed SNP-chip analysis.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

The pathogenesis of diffuse large B-cell lymphomas (DLBCL) is only partly understood. We analyzed 148 DLBCL by single nucleotide polymorphism (SNP)-chips to characterize genomic imbalances. Seventy-nine … cases were of the germinal center B-cell like (GCB) type of DLBCL, 49 of the activated B-cell like (ABC) subtype and 20 were unclassified DLBCL. Twenty-four regions of recurrent genomic gains and 38 regions of recurrent genomic losses were identified over the whole cohort, with a median of 25 imbalances per case for ABC-DLBCL and 19 per case for GCB-DLBCL. Several recurrent copy number changes showed differential frequencies in the GCB- and ABC-DLBCL subgroups, including gains of HDAC7A predominantly in GCB-DLBCL (38% of cases) and losses of BACH2 and CASP8AP2 predominantly in ABC-DLBCL (35%), hinting at disparate pathogenetic mechanisms in these entities. Correlating gene expression and copy number revealed a strong gene dosage effect in all tumors, with 34% of probesets showing a concordant expression change in affected regions. Two new potential tumor suppressor genes emerging from the analysis, CASP3 and IL5RA, were sequenced in ten and 16 candidate cases, respectively. However, no mutations were found, pointing to a potential haploinsufficiency effect of these genes, considering their reduced expression in cases with deletions. Our study thus describes differences and similarities in the landscape of genomic aberrations in the DLBCL subgroups in a large collection of cases, confirming already known targets, but also discovering novel copy number changes with possible pathogenetic relevance.

Authors: R. Scholtysik, M. Kreuz, M. Hummel, M. Rosolowski, M. Szczepanowski, W. Klapper, M. Loeffler, L. Trumper, R. Siebert, R. Kuppers

Date Published: 1st Mar 2015

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Importance The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection …n and risk reduction in this population. Objective To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P \textless .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P \textless .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P \textless .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P \textless .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. Conclusions and Relevance Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

Authors: Valentina Silvestri, Goska Leslie, Daniel R. Barnes, Bjarni A. Agnarsson, Kristiina Aittomäki, Elisa Alducci, Irene L. Andrulis, Rosa B. Barkardottir, Alicia Barroso, Daniel Barrowdale, Javier Benitez, Bernardo Bonanni, Ake Borg, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Carlo Capalbo, Ian Campbell, Wendy K. Chung, Kathleen B. M. Claes, Sarah V. Colonna, Laura Cortesi, Fergus J. Couch, Miguel de La Hoya, Orland Diez, Yuan Chun Ding, Susan Domchek, Douglas F. Easton, Bent Ejlertsen, Christoph Engel, D. Gareth Evans, Lidia Feliubadalò, Lenka Foretova, Florentia Fostira, Lajos Géczi, Anne-Marie Gerdes, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Eric Hahnen, Frans B. L. Hogervorst, John L. Hopper, Peter J. Hulick, Claudine Isaacs, Angel Izquierdo, Paul A. James, Ramunas Janavicius, Uffe Birk Jensen, Esther M. John, Vijai Joseph, Irene Konstantopoulou, Allison W. Kurian, Ava Kwong, Elisabetta Landucci, Fabienne Lesueur, Jennifer T. Loud, Eva Machackova, Phuong L. Mai, Keivan Majidzadeh-A, Siranoush Manoukian, Marco Montagna, Lidia Moserle, Anna Marie Mulligan, Katherine L. Nathanson, Heli Nevanlinna, Joanne Ngeow Yuen Ye, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Laura Papi, Sue K. Park, Inge Sokilde Pedersen, Pedro Perez-Segura, Annabeth H. Petersen, Pedro Pinto, Berardino Porfirio, Miquel Angel Pujana, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Barak Rosenzweig, Maria Rossing, Marta Santamariña, Rita K. Schmutzler, Leigha Senter, Jacques Simard, Christian F. Singer, Angela R. Solano, Melissa C. Southey, Linda Steele, Zoe Steinsnyder, Dominique Stoppa-Lyonnet, Yen Yen Tan, Manuel R. Teixeira, Soo H. Teo, Mary Beth Terry, Mads Thomassen, Amanda E. Toland, Sara Torres-Esquius, Nadine Tung, Christi J. van Asperen, Ana Vega, Alessandra Viel, Jeroen Vierstraete, Barbara Wappenschmidt, Jeffrey N. Weitzel, Greet Wieme, Sook-Yee Yoon, Kristin K. Zorn, Lesley McGuffog, Michael T. Parsons, Ute Hamann, Mark H. Greene, Judy A. Kirk, Susan L. Neuhausen, Timothy R. Rebbeck, Marc Tischkowitz, Georgia Chenevix-Trench, Antonis C. Antoniou, Eitan Friedman, Laura Ottini

Date Published: 2nd Jul 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Charts and LMS tables of transfontanellar and transvertical ear-to-ear distances for gestational age
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

Introduction: To date cranial development has only been described by analyzing occipitofrontal circumference (OFC). More precise methods of determining head measurements have not been widely adopted. … The use of additional measurements has the potential to better account for the three-dimensional structure of the head. Our aim was to put forward centile curves of such measurements for gestational age along with a compound head volume index. Methods: We created generalized additive models for location, scale, and shape of two ear-to-ear distances (EED), transfontanellar (fEED) and transvertical (vEED), from birth anthropometric data. Same was done for OFC, crown-heel length, and birth weight to allow for comparison of our models with growth charts by Voigt et al. and Fenton and Kim. Results: Growth charts and tables of LMS parameters for fEED and vEED were derived from 6,610 patients admitted to our NICU and 625 healthy term newborns. With increasing gestational age EEDs increase about half as fast compared to OFC in absolute terms, their relative growths are fairly similar. Discussion: Differences to the charts by Fenton and Kim are minute. Tape measurements, such as fEED or vEED can be added to routine anthropometry at little extra costs. These charts may be helpful for following and evaluating head sizes and growth of preterm and term infants in three dimensions.

Authors: Nancy Arnold, Rudolf Georg Ascherl, Ulrich Herbert Thome

Date Published: 1st May 2022

Publication Type: Journal article

Chemotherapy for intracranial ependymoma in adults.
GGN - German Glioma Network

Abstract (Expand)

BACKGROUND: Ependymal tumors in adults are rare, accounting for less than 4% of primary tumors of the central nervous system in this age group. The low prevalence of intracranial ependymoma in adults … limits the ability to perform clinical trials. Therefore, treatment decisions are based on small, mostly retrospective studies and the role of chemotherapy has remained unclear. METHODS: We performed a retrospective study on 17 adult patients diagnosed with intracranial World Health Organisation grade II or III ependymoma, who were treated with chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by applying Macdonald criteria. Progression-free (PFS) and overall survival (OS) were calculated from start of chemotherapy, using the Kaplan-Meier method. RESULTS: Eleven patients had supratentorial and 6 infratentorial tumors. Ten patients were treated with temozolomide (TMZ), 3 with procarbazine/lomustine/vincristine (PCV), 3 with platinum-based chemotherapy and 1 patient received epirubicin/ifosfamide. Response rates were as follows: TMZ 8/10 stable disease; PCV 3/3 stable disease; platinum-based chemotherapy 1/3 partial response; epirubicin/ifosfamide 1/1 complete response. PFS rates at 6, 12 and 24 months were 52.9, 35.3 and 23.5%. OS rates at 6, 12 and 24 months were 82.4, 82.4 and 70.1%. There was no indication for a favourable prognostic role of O(6)-methylguanyl-DNA-methyltransferase (MGMT) promoter methylation which was detected in 3/12 investigated tumors. CONCLUSIONS: Survival outcomes in response to chemotherapy in adult intracranial ependymoma patients vary substantially, but individual patients may respond to any kind of chemotherapy. There were too few patients to compare survival data between chemotherapeutic subgroups.

Authors: D. Gramatzki, P. Roth, J. Felsberg, S. Hofer, E. J. Rushing, B. Hentschel, M. Westphal, D. Krex, M. Simon, O. Schnell, W. Wick, G. Reifenberger, M. Weller

Date Published: 23rd Apr 2016

Publication Type: Journal article

Human Diseases: adult brain ependymoma

Cholesterol esterification in plasma as a biomarker for liver function and prediction of mortality
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Advanced stages of liver cirrhosis lead to a dramatically increased mortality. For valid identification of these patients suitable biomarkers are essential. The most important biomarkers for …r liver function are bilirubin and prothrombin time expressed as International Normalized Ratio (INR). However, the influence of several anticoagulants on the prothrombin time limits its diagnostic value. Aim of this study was the evaluation of cholesterol esterification (CE) fraction (esterified cholesterol vs. total cholesterol) as an alternative biomarker for liver synthesis and mortality prediction. Under physiological conditions the CE fraction in blood is closely regulated by lecithin-cholesterol acyltransferase (LCAT) which is produced in the liver. METHODS One hundred forty-two patients with liver disease clinically considered for orthotopic liver transplant for different indications were enrolled in the study. One patient was excluded because of the intake of a direct oral factor Xa inhibitor which has a strong impact on prothrombin time. RESULTS Results of CE fraction were in good agreement with INR (R(2) = 0.73; p \textless 0.001). In patients who died or survived within three months mean CE fraction was 56% vs. 74% (p \textless 0.001) and mean INR was 2.0 vs. 1.3 (p \textless 0.001), respectively. The predictive value of CE fraction for three-month mortality risk was higher compared to INR (p = 0.04). Results for one-year mortality were comparable. CONCLUSIONS The cholesterol esterification fraction is a valid biomarker for liver synthesis and allows reliable prediction of mortality. In contrast to INR, it is independent of anticoagulation and other analytical limitations of coagulation tests.

Authors: Thorsten Kaiser, Benedict Kinny-Köster, Michael Bartels, Thomas Berg, Markus Scholz, Cornelius Engelmann, Daniel Seehofer, Susen Becker, Uta Ceglarek, Joachim Thiery

Date Published: 1st Dec 2017

Publication Type: Journal article

CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: The role of rituximab in combination with different CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy regimens in young patients with good-prognosis diffuse … large-B-cell lymphoma remains to be defined. We aimed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients. METHODS: 824 patients who were from 18 countries; aged 18-60 years; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index (IPI), stage II-IV disease, or stage I disease with bulk were enrolled. These patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n=413) or to six cycles of CHOP-like chemotherapy alone (n=411). Bulky and extranodal sites received additional radiotherapy. The primary endpoint was event-free survival; secondary endpoints were response, progression under therapy, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat and per protocol. This trial is registered at http://www.clinicaltrials.gov, NCT 00064116. FINDINGS: After a median follow-up of 34 months (range 0.03-61), patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone (79% [95% CI 75-83] vs 59% [54-64]; difference between groups 20% [13-27], log-rank p<0.0001), and had increased 3-year overall survival (93% [90-95] vs 84% [80-88]; difference between groups 9% [3-13], log-rank p=0.0001). Event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI: after chemotherapy and rituximab, a favourable subgroup (ie, IPI=0, no bulk) could be defined from a less-favourable subgroup (ie, IPI=1 or bulk, or both). Groups did not differ in the frequency of adverse events. INTERPRETATION: Rituximab added to six cycles of CHOP is an effective treatment for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows for a more refined therapeutic approach for these patients.

Authors: M. Pfreundschuh, L. Trumper, A. Osterborg, R. Pettengell, M. Trneny, K. Imrie, D. Ma, D. Gill, J. Walewski, P. L. Zinzani, R. Stahel, S. Kvaloy, O. Shpilberg, U. Jaeger, M. Hansen, T. Lehtinen, A. Lopez-Guillermo, C. Corrado, A. Scheliga, N. Milpied, M. Mendila, M. Rashford, E. Kuhnt, M. Loeffler

Date Published: 2nd May 2006

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, diffuse large B-cell lymphoma

CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group.
GLA - German Lymphoma Alliance, MMML Demonstrators - Molecular Mechanisms in Malignant Lymphomas - Demonstrators of Personalized Medicine

Abstract (Expand)

BACKGROUND: The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young … patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects. METHODS: In the randomised open-label MInT study, patients from 18 countries (aged 18-60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II-IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907. FINDINGS: The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0.03-119), 6-year event-free survival was 55.8% (95% CI 50.4-60.9; 166 events) for patients assigned to chemotherapy alone and 74.3% (69.3-78.6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18.5%, 11.5-25.4, log-rank p<0.0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84.3% [95% CI 74.2-90.7] vs 71.0% [65.1-76.1], log-rank p=0.005). 18 (4.4%, 95% CI 2.6-6.9) second malignancies occurred in the chemotherapy-alone group and 16 (3.9%, 2.2-6.2) in the chemotherapy and rituximab group (Fisher's exact p=0.730). INTERPRETATION: Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone. FUNDING: Hoffmann-La Roche.

Authors: M. Pfreundschuh, E. Kuhnt, L. Trumper, A. Osterborg, M. Trneny, L. Shepherd, D. S. Gill, J. Walewski, R. Pettengell, U. Jaeger, P. L. Zinzani, O. Shpilberg, S. Kvaloy, P. de Nully Brown, R. Stahel, N. Milpied, A. Lopez-Guillermo, V. Poeschel, S. Grass, M. Loeffler, N. Murawski

Date Published: 24th Sep 2011

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, diffuse large B-cell lymphoma

Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans
Genetical Statistics and Systems Biology

Abstract (Expand)

Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus … (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.

Authors: Lesca M. Holdt, Anika Stahringer, Kristina Sass, Garwin Pichler, Nils A. Kulak, Wolfgang Wilfert, Alexander Kohlmaier, Andreas Herbst, Bernd H. Northoff, Alexandros Nicolaou, Gabor Gäbel, Frank Beutner, Markus Scholz, Joachim Thiery, Kiran Musunuru, Knut Krohn, Matthias Mann, Daniel Teupser

Date Published: 1st Nov 2016

Publication Type: Journal article

Circulating Adipokine VASPIN Is Associated with Serum Lipid Profiles in Humans
Genetical Statistics and Systems Biology

Abstract (Expand)

VASPIN, visceral adipose tissue-derived serpin, is an adipokine ameliorating insulin resistance in obesity. Here, we investigated the role of VASPIN and its genetic variants in lipid metabolism. We … measured serum VASPIN concentrations by ELISA in 823 metabolically well-characterized Caucasian subjects (Sorbs from Germany). Furthermore, we genotyped 30 representative single nucleotide polymorphisms (SNP) in two independent cohorts with metabolic phenotyping, the Sorbs (N = 823) and Leipzig (N = 919), and conducted genotype-phenotype association analyses. Circulating VASPIN strongly correlated with triacylglycerol levels (TAG; p = 1.079 \times 10-11 ), and moderately with apolipoprotein A1 and low-density lipoprotein cholesterol (p = 0.026). Genetic variants in VASPIN were nominally associated with cholesterol, high-density and low-density lipoprotein (HDL-chol, LDL-chol), lipoprotein A, and apolipoprotein B as well as with TAG and free fatty acids (all p \textless 0.05 adjusted for age, sex, and body mass index [BMI]). Mendelian randomization analysis using VASPIN SNP as an instrumental variable showed borderline influence of VASPIN on LDL-chol levels (p = 0.05). Associations of VASPIN and its genetic variation with metabolic traits suggest a role of VASPIN in human lipid metabolism.

Authors: Jana Breitfeld, Norman Wiele, Beate Gutsmann, Michael Stumvoll, Matthias Blüher, Markus Scholz, Peter Kovacs, Anke Tönjes

Date Published: 18th Mar 2019

Publication Type: Journal article

Circulating levels of TNF receptor II are prognostic for patients with peripheral T-cell non-Hodgkin lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

PURPOSE: Peripheral T-cell non-Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated … with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs. EXPERIMENTAL DESIGN: Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay. RESULTS: Patients characterized by TNFRI-609GG (rs4149570) showed a trend toward better event free survival [EFS; univariate: P = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99-3.14 with P = 0.056]. A protective role of IL-10-1087A, -824T, and -597A reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII >/=2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: P = 0.0034; multivariate: HR, 2.07; CI, 0.92-4.70 with P = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: P = 0.00068; multivariate: HR, 2.49; CI, 1.22-5.08 with P = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different. CONCLUSIONS: Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs.

Authors: C. Heemann, M. Kreuz, I. Stoller, N. Schoof, F. von Bonin, M. Ziepert, M. Loffler, W. Jung, M. Pfreundschuh, L. Trumper, D. Kube

Date Published: 1st Jul 2012

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

Circulating Nampt and RBP4 levels in patients with carotid stenosis undergoing carotid endarterectomy (CEA)
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnObesity is a risk factor for atherosclerotic vascular disease. Altered adipokine secretion, including increased production of nicotinamide phosphoribosyltransferase … (Nampt) and retinol binding protein 4 (RBP4) may link adipose tissue dysfunction to cardiovascular complications.\backslashr\backslashnMETHODS\backslashr\backslashnWe determined Nampt and RBP4 serum concentrations in 193 consecutive patients with carotid stenosis prior to carotid endarterectomy (CEA) in relation to recently experienced ischemic events, markers of atherosclerosis and obesity, as well as anthropometric and clinical characteristics.\backslashr\backslashnRESULTS\backslashr\backslashnNampt but not RBP4 was significantly higher in symptomatic patients who experienced an ischemic event within 6 months before surgery compared to asymptomatic patients (p=0.001). In multivariate regression analysis Nampt was the only independent predictor of symptomatic carotid stenosis. Nampt correlated with peripheral leukocyte blood count (p\textless0.0001) and with the number of macrophages/foam cells within carotid plaques (p=0.042). However, Nampt and RBP4 serum concentrations did not correlate with the maximum percentage of carotid stenosis.\backslashr\backslashnCONCLUSION\backslashr\backslashnOur data suggest circulating Nampt as an independent predictor of recently experienced ischemic events in patients with carotid stenosis despite the lack of an association between Nampt and carotid atherosclerosis severity. BACKGROUND Obesity is a risk factor for atherosclerotic vascular disease. Altered adipokine secretion, including increased production of nicotinamide phosphoribosyltransferase (Nampt) and retinol binding protein 4 (RBP4) may link adipose tissue dysfunction to cardiovascular complications. METHODS We determined Nampt and RBP4 serum concentrations in 193 consecutive patients with carotid stenosis prior to carotid endarterectomy (CEA) in relation to recently experienced ischemic events, markers of atherosclerosis and obesity, as well as anthropometric and clinical characteristics. RESULTS Nampt but not RBP4 was significantly higher in symptomatic patients who experienced an ischemic event within 6 months before surgery compared to asymptomatic patients (p=0.001). In multivariate regression analysis Nampt was the only independent predictor of symptomatic carotid stenosis. Nampt correlated with peripheral leukocyte blood count (p\textless0.0001) and with the number of macrophages/foam cells within carotid plaques (p=0.042). However, Nampt and RBP4 serum concentrations did not correlate with the maximum percentage of carotid stenosis. CONCLUSION Our data suggest circulating Nampt as an independent predictor of recently experienced ischemic events in patients with carotid stenosis despite the lack of an association between Nampt and carotid atherosclerosis severity.

Authors: Gabriela Aust, Migle Uptaite-Patapoviene, Markus Scholz, Olaf Richter, Silvio Rohm, Matthias Blüher

Date Published: 1st Jun 2011

Publication Type: Journal article

Circulating oxytocin is genetically determined and associated with obesity and impaired glucose tolerance
Genetical Statistics and Systems Biology

Abstract (Expand)

CONTEXT Despite the emerging evidence on the role of oxytocin (OXT) in metabolic diseases, there is a lack of well powered studies addressing the relationship of circulating OXT with obesity and diabetes. …. OBJECTIVES AND DESIGN Here, we measured OXT in a study cohort (n=721; 396 women, 325 men; mean age\pmSD - 47.7\pm15.2 years) with sub-phenotypes related to obesity including anthropometric traits such as body mass index (BMI; mean\pmSD - 47.7\pm15.2 kg/m2), waist-to-hip-ratio (WHR; 0.88\pm0.09), blood parameters (glucose - 5.32\pm0.50 mmol/l, insulin - 5.3\pm3.3 µU/ml, lipids) and oral glucose tolerance test (OGTT) to clarify the association with OXT. We also tested in a genome-wide association study (GWAS) whether the inter-individual variation in OXT serum levels might be explained by genetic variation. RESULTS The OXT concentration was increased in subjects with elevated BMI and positively correlated with WHR, waist circumference and triglyceride levels. The OXT concentration in subjects with BMI\textless25 kg/m2 was significantly lower (n=256; 78.6 pg/ml) than in subjects with a BMI between 25-30 kg/m2 (n=314; 98.5 pg/ml, p=6x10-6) and with BMI\textgreater30 kg/m2 (n=137; 106.4 pg/ml, p=8x10-6). OXT levels were also positively correlated with plasma glucose and insulin and were elevated in subjects with impaired glucose tolerance (p=4.6x10-3). Heritability of OXT was estimated to 12.8%. In a GWAS, two hits in linkage disequilibrium close (19kb) to the OXT reached genome-wide significant association (top-hit rs12625893, p=3.1x10-8, explained variance 3%). CONCLUSIONS Our data show that OXT is genetically affected by a variant in OXT and is associated with obesity and impaired glucose tolerance.

Authors: Mark Florian Joachim Weingarten, Markus Scholz, Tobias Wohland, Katrin Horn, Michael Stumvoll, Peter Kovacs, Anke Tönjes

Date Published: 1st Nov 2019

Publication Type: Journal article

Classifying prostate cancer malignancy by quantitative histomorphometry.
ProstataCA

Abstract (Expand)

PURPOSE: Prostate cancer is routinely graded according to the Gleason grading scheme. This scheme is predominantly based on the textural appearance of aberrant glandular structures. Gleason grade is … difficult to standardize and often leads to discussion due to interrater and intrarater disagreement. Thus, we investigated whether digital image based automated quantitative histomorphometry could be used to achieve a more standardized, reproducible classification outcome. MATERIALS AND METHODS: In a proof of principle study we developed a method to evaluate digitized histological images of single prostate cancer regions in hematoxylin and eosin stained sections. Preprocessed color images were subjected to color deconvolution, followed by the binarization of obtained hematoxylin related image channels. Highlighted neoplastic epithelial gland related objects were morphometrically assessed by a classifier based on 2 calculated quantitative and objective geometric measures, that is inverse solidity and inverse compactness. The procedure was then applied to the prostate cancer probes of 125 patients. Each probe was independently classified for Gleason grade 3, 4 or 5 by an experienced pathologist blinded to image analysis outcome. RESULTS: Together inverse compactness and inverse solidity were adequate discriminatory features for a powerful classifier that distinguished Gleason grade 3 from grade 4/5 histology. The classifier was robust on sensitivity analysis. CONCLUSIONS: Results suggest that quantitative and interpretable measures can be obtained from image based analysis, permitting algorithmic differentiation of prostate Gleason grades. The method must be validated in a large independent series of specimens.

Authors: M. Loeffler, L. Greulich, P. Scheibe, P. Kahl, Z. Shaikhibrahim, U. D. Braumann, J. P. Kuska, N. Wernert

Date Published: 20th Mar 2012

Publication Type: Not specified

Human Diseases: prostate cancer

Clinical and lifestyle related factors influencing whole blood metabolite levels -- A comparative analysis of three large cohorts
Genetical Statistics and Systems Biology

Abstract (Expand)

Objective Human blood metabolites are influenced by a number of lifestyle and environmental factors. Identification of these factors and the proper quantification of their relevance provides insights …s into human biological and metabolic disease processes, is key for standardized translation of metabolite biomarkers into clinical applications, and is a prerequisite for comparability of data between studies. However, so far only limited data exist from large and well-phenotyped human cohorts and current methods for analysis do not fully account for the characteristics of these data. The primary aim of this study was to identify, quantify and compare the impact of a comprehensive set of clinical and lifestyle related factors on metabolite levels in three large human cohorts. To achieve this goal, we improve current methodology by developing a principled analysis approach, which could be translated to other cohorts and metabolite panels. Methods 63 Metabolites (amino acids, acylcarnitines) were quantified by liquid chromatography tandem mass spectrometry in three cohorts (total N~=~16,222). Supported by a simulation study evaluating various analytical approaches, we developed an analysis pipeline including preprocessing, identification, and quantification of factors affecting metabolite levels. We comprehensively identified uni- and multivariable metabolite associations considering 29 environmental and clinical factors and performed metabolic pathway enrichment and network analyses. Results Inverse normal transformation of batch corrected and outlier removed metabolite levels accompanied by linear regression analysis proved to be the best suited method to deal with the metabolite data. Association analyses revealed numerous uni- and multivariable significant associations. 15 of the analyzed 29 factors explained {\textgreater}1{\%} of variance for at least one of the metabolites. Strongest factors are application of steroid hormones, reticulocytes, waist-to-hip ratio, sex, haematocrit, and age. Effect sizes of factors are comparable across studies. Conclusions We introduced a principled approach for the analysis of MS data allowing identification, and quantification of effects of clinical and lifestyle factors with metabolite levels. We detected a number of known and novel associations broadening our understanding of the regulation of the human metabolome. The large heterogeneity observed between cohorts could almost completely be explained by differences in the distribution of influencing factors emphasizing the necessity of a proper confounder analysis when interpreting metabolite associations.

Authors: Carl Beuchel, Susen Becker, Julia Dittrich, Holger Kirsten, Anke Toenjes, Michael Stumvoll, Markus Loeffler, Holger Thiele, Frank Beutner, Joachim Thiery, Uta Ceglarek, Markus Scholz

Date Published: 17th Aug 2019

Publication Type: Not specified

Clinical Impact of the Cell-of-Origin Classification and the MYC/ BCL2 Dual Expresser Status in Diffuse Large B-Cell Lymphoma Treated Within Prospective Clinical Trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group.
GLA - German Lymphoma Alliance

Abstract (Expand)

Purpose To explore the prognostic impact and interdependence of the cell-of-origin (COO) classification, dual expression (DE) of MYC and BCL2 proteins, and MYC, BCL2, and BCL6 translocations in two … prospectively randomized clinical trials of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Overall, 452 formalin-fixed paraffin-embedded samples from two prospective, randomized DLBCL trials (RICOVER-60, prospective, randomized study for patients > 60 years, all IPI groups; and R-MegaCHOEP, prospective, randomized study for patients </= 60 years with age-adjusted IPI 2,3) of the German High-Grade Non-Hodgkin Lymphoma Study Group were analyzed with the Lymph2Cx assay for COO classification, with immunohistochemistry for MYC and BCL2, and with fluorescent in situ hybridization for MYC, BCL2, and BCL6 rearrangements. Results COO classification was successful in 414 of 452 samples. No significant differences with respect to COO (activated B-cell [ABC]-like DLBCL v germinal center B-cell [GCB]-like DLBCL) were observed in event-free survival, progression-free survival, and overall survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the RICOVER-60 trial. Also, no differences with respect to COO were observed in multivariable analyses adjusted for International Prognostic Index factors in event-free survival (hazard ratio [HR] of ABC-like disease v GCB-like disease, 1.0; 95% CI, 0.6 to 1.6; P = .93), progression-free survival (HR, 1.1; 95% CI, 0.6 to 1.8; P = .82), and overall survival (HR, 1.0; 95% CI, 0.6 to 1.8; P = .96). Similar results were observed in the R-MegaCHOEP trial. In patients treated with R-CHOP, DE status was associated with significantly inferior survival compared with nonDE within the GCB, but not within the ABC subgroup. DE status was associated with significantly inferior outcome compared with patients with ABC-like DLBCL without DE (5-year PFS rate, 39% [95% CI,19% to 59%] v 68% [95% CI, 52% to 85%]; P = .03) and compared with patients with GCB-like DLBCL without DE. When data from patients with nonDE were analyzed separately, the outcome of patients in the ABC subgroup was inferior to that of patients in the GCB subgroup (5-year PFS rate, 68% [95% CI, 52% to 85%] v 85% [95% CI, 74% to 96%]; P = .04). Conclusion COO profiling in two prospective randomized DLBCL trials failed to identify prognostic subgroups, whereas dual expression of MYC and BCL2 was predictive of poor survival. Evaluation of prognostic or predictive biomarkers in the management of DLBCL, such as the COO, within prospective clinical trials will be important in the future.

Authors: A. M. Staiger, M. Ziepert, H. Horn, D. W. Scott, T. F. E. Barth, H. W. Bernd, A. C. Feller, W. Klapper, M. Szczepanowski, M. Hummel, H. Stein, D. Lenze, M. L. Hansmann, S. Hartmann, P. Moller, S. Cogliatti, G. Lenz, L. Trumper, M. Loffler, N. Schmitz, M. Pfreundschuh, A. Rosenwald, G. Ott

Date Published: 1st Aug 2017

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Clinical, pathological and genetic features of follicular lymphoma grade 3A: a joint analysis of the German low-grade and high-grade lymphoma study groups GLSG and DSHNHL.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: Histologically, follicular lymphoma (FL) grades 1, 2 and 3A are composed of two distinct cell types, centroblasts and centrocytes. FL grade 3B is composed only of centroblasts and has been … shown to differ in immunophenotype and genetics from FL that contain centrocytes. We aimed to understand the pathogenetic and clinical relation between FL grade 3A to FL grade 1/2 on the one hand and FL grade 3B on the other hand. PATIENTS AND METHODS: Trial patients with long-term follow-up and diagnosis of FL grade 3 were selected and samples underwent a second central pathological review using a multiple-observer approach to assess grading. RESULTS: Interobserver variability for diagnosing FL grade 3 was high. FL grade 3A frequently harbored areas of FL grade 1/2 within the same tissue specimen. FL grade 3B rarely coexisted with grade 1/2 or 3A, suggesting divergent pathogenesis. There was no statistically significant difference in outcome between 47 cases of FL grade 3A and 14 cases of grade 3B. Compared with grade 1/2 FL, both groups showed longer progression-free survival without late events, especially after immunochemotherapy; this outcome difference was retained after adjustment for clinical prognostic factors. The subgroup of FL grade 3A with an additional FL grade 1/2 component or a translocation t(14;18) showed a poorer outcome. In contrast, the FL grade 3A lacking t(14;18) and of localized stage resembled the pediatric type of FL and showed a very good outcome. FL3 with MYC breaks showed a poor outcome. CONCLUSIONS: The results suggest that first-line immunochemotherapy might allow long-lasting remissions in a subgroup of FL grade 3A similar to diffuse large B-cell lymphoma. Within FL3A, prognostic subgroups can be identified by analyzing for coexisting FL1/2 and MYC breaks.

Authors: K. Koch, E. Hoster, M. Ziepert, M. Unterhalt, G. Ott, A. Rosenwald, M. L. Hansmann, W. Bernd, H. Stein, V. Poschel, M. Dreyling, L. Trumper, M. Loffler, N. Schmitz, W. Hiddemann, M. Pfreundschuh, W. Klapper

Date Published: 28th Apr 2016

Publication Type: Not specified

Human Diseases: follicular lymphoma

CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: To describe incidence, risk factors, and influence of treatment on occurrence of central nervous system (CNS) relapse or progression in younger patients with aggressive B-cell lymphoma. … PATIENTS AND METHODS: We analyzed 2210 patients with aggressive B-cell lymphoma treated on various studies for CNS relapse/progression. Treatment consisted of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) +/- etoposide. Six hundred and twenty patients also received rituximab. CNS prophylaxis was intrathecal methotrexate on High-CHOEP and MegaCHOEP phase III studies if upper neck, head, bone marrow, or testes were involved. RESULTS: Fifty-six of 2196 patients (2.6%) developed CNS disease. It occurred early (median 7.0 months), median survival was 5.0 months. Patients with age-adjusted International Prognostic Index (aaIPI) 0 or 1 treated with rituximab showed a low risk for CNS disease (2-year rates: 0% or 0.5%), and rituximab decreased the risk (relative risk 0.3, 95% confidence interval 0.1-0.9, P = 0.029). Patients with aaIPI 2 or 3 showed a moderate risk (4.2%-9.7%) and no significant reduction of CNS disease with rituximab. CNS prophylaxis was of no significant benefit. CONCLUSIONS: In younger patients with aaIPI 0 or 1, CNS relapse/progression is very rare; in patients with aaIPI 2 or 3, the risk is higher (up to 10%) and requires new diagnostic strategies and treatment.

Authors: N. Schmitz, S. Zeynalova, B. Glass, U. Kaiser, E. Cavallin-Stahl, M. Wolf, M. Haenel, M. Loeffler, L. Truemper, M. Pfreundschuh

Date Published: 13th Oct 2011

Publication Type: Not specified

Human Diseases: B-cell lymphoma

CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).
GLA - German Lymphoma Alliance

Abstract (Expand)

One thousand two hundred twenty-two patients treated in the Rituximab with CHOP over age 60 years (RICOVER-60) trial were examined for central nervous system (CNS) disease developing during first-line … therapy or after a complete or partial remission had been achieved. Patients received 6 or 8 courses of CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) administered every 2 weeks (CHOP-14) with or without rituximab. CNS prophylaxis for patients with involvement of bone marrow, testes, upper neck, or head consisted of intrathecal (i.th.) methotrexate (days 1 and 5 of first 2 courses). Fifty-eight cases of lymphoma in the CNS were observed (36/609 patients in the CHOP-14 and 22/608 patients in the arituximab-CHOP-14 [R-CHOP-14] arm). The estimated 2-year incidence of CNS disease was 6.9% (confidence interval [CI] 4.5; 9.3) after CHOP-14 and 4.1% (CI 2.3; 5.9) after R-CHOP-14. R-CHOP reduced the relative risk for CNS disease to 0.58 (95% CI 0.3; 1.0, P = .046). Cox regression analysis identified "involvement of more than 1 extranodal site" and "B-symptoms" as significant risk factors for CNS disease. Patients treated with R-CHOP-14 did not show any benefit from i.th. methotrexate. We conclude that elderly patients with aggressive CD20-positive lymphoma show a significantly lower incidence of CNS disease if treated with R-CHOP-14 instead of CHOP-14. Intrathecal methotrexate has no role in preventing CNS disease for patients treated with combined immunochemotherapy (R-CHOP-14)--with the possible exception of patients with testicular involvement.

Authors: V. Boehme, N. Schmitz, S. Zeynalova, M. Loeffler, M. Pfreundschuh

Date Published: 23rd Apr 2009

Publication Type: Not specified

Human Diseases: lymphoma

CNS International Prognostic Index: A Risk Model for CNS Relapse in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP.
GLA - German Lymphoma Alliance

Abstract (Expand)

PURPOSE: To develop and validate a risk score for relapse in the CNS in patients with diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: A total of 2,164 patients (18 to 80 years old) with … aggressive B-cell lymphomas (80% DLBCL) treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like chemotherapy, who were enrolled in studies from the German High-Grade Non-Hodgkin Lymphoma Study Group and the MabThera International Trial, were analyzed for occurrence of relapse/progression in the CNS. The resulting risk model was validated in an independent data set of 1,597 patients with DLBCL identified in the British Columbia Cancer Agency Lymphoid Cancer database. RESULTS: The risk model consists of the International Prognostic Index (IPI) factors in addition to involvement of kidneys and/or adrenal glands (CNS-IPI). In a three-risk group model, the low-risk group (46% of all patients analyzed), the intermediate-risk group (41%), and the high-risk group (12%) showed 2-year rates of CNS disease of 0.6% (CI, 0% to 1.2%), 3.4% (CI, 2.2% to 4.4%), and 10.2% (CI, 6.3% to 14.1%), respectively. Patients from the validation British Columbia Cancer Agency data set showed similar rates of CNS disease for low-risk (0.8%; CI, 0.0% to 1.6%), intermediate-risk (3.9%; CI, 2.3% to 5.5%), and high-risk (12.0%; CI, 7.9% to 16.1%) groups. CONCLUSION: The CNS-IPI is a robust, highly reproducible tool that can be used to estimate the risk of CNS relapse/progression in patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Close to 90% of patients with DLBCL belong to the low- and intermediate-risk groups and have a CNS relapse risk < 5%; they may be spared any diagnostic and therapeutic intervention. In contrast, those in the high-risk group have a > 10% risk of CNS relapse and should be considered for CNS-directed investigations and prophylactic interventions.

Authors: N. Schmitz, S. Zeynalova, M. Nickelsen, R. Kansara, D. Villa, L. H. Sehn, B. Glass, D. W. Scott, R. D. Gascoyne, J. M. Connors, M. Ziepert, M. Pfreundschuh, M. Loeffler, K. J. Savage

Date Published: 10th Sep 2016

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Cohort profile: The Leipzig Research Center for Civilization Diseases–Heart study (LIFE-Heart)
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Markus Scholz, Sylvia Henger, Frank Beutner, Andrej Teren, Ronny Baber, Anja Willenberg, Uta Ceglarek, Janne Pott, Ralph Burkhardt, Joachim Thiery

Date Published: 3rd Aug 2020

Publication Type: Journal article

Combined effects of different interleukin-28B gene variants on the outcome of dual combination therapy in chronic hepatitis C virus type 1 infection
Genetical Statistics and Systems Biology

Abstract (Expand)

In patients with chronic hepatitis C virus (HCV) infection, several variants of the interleukin-28B (IL28B) gene have been shown to correlate significantly with a sustained virologic response (SVR). … Recent evidence shows that determination of one single IL28B polymorphism, rs12979860, is sufficient for predicting treatment outcome. We examined whether the combined determination of the IL28B single-nucleotide polymorphisms (SNPs), rs12979860, rs8099917, rs12980275, and rs8103142, might improve the prediction of SVR in patients with HCV. In the study cohort, 54% of 942 patients with chronic HCV type 1 infection had SVR. The IL28B SNPs, rs12979860CC and rs8099917TT, correlated significantly with SVR (68% and 62%). The SNPs, rs12980275 and rs8103142, were in strong linkage disequilibrium with rs12979860 and were not included in further analysis. In homozygous carriers of the rs12979860 responder allele C, additional genotyping of the rs8099917 SNP had no effect on response prediction, whereas in carriers of the rs12979860 nonresponder allele, the rs8099917 SNP improved the response prediction. In heterozygous carriers of the rs12979860 nonresponder T allele, SVR rates were 55% in the presence of the rs8099917TT genotype and 40% in patients carrying the rs8099917 TG or GG genotype. Analysis of an independent confirmation cohort of 377 HCV type 1-infected patients verified the significant difference in SVR rates between the combined genotypes, rs12979860CT/rs8099917TT and rs12979860CT/rs8099917TG (38% versus 21%; P = 0.018). Conclusion: Treatment outcome prediction could not be improved in homozygous carriers of the IL28B rs12979860 C responder allele by the additional determination of the rs8099917 SNP. There is evidence that a significant proportion of heterozygous carriers of the rs12979860 T nonresponder allele can profit with respect to SVR prediction by further determination of the rs8099917 SNP. (HEPATOLOGY 2012;55:1700-1710).

Authors: Janett Fischer, Stephan Böhm, Markus Scholz, Tobias Müller, Heiko Witt, Jacob George, Christoph Sarrazin, Simone Susser, Eckart Schott, Vijayaprakash Suppiah, David R. Booth, Graeme J. Stewart, Florian van Bömmel, Annika Brodzinski, Balazs Fülöp, Pascal Migaud, Thomas Berg

Date Published: 1st Jun 2012

Publication Type: Journal article

Combined serial section-based 3D reconstruction of cervical carcinoma invasion using H&E/p16INK4a/CD3 alternate staining.
ProstataCA

Abstract (Expand)

BACKGROUND: Malignant growth and invasiveness of cancers is a function of both intratumoral and stromal factors. The accessibility to nutrients, oxygen and growth factors, the stromal composition, and … the interference with the immune system all shape the tumor invasion front. A recent study has shown a prognostic difference with respect to different invasion patterns analyzed on histological specimens of cervical cancers. The present study analyzes the spatial organization of a cervical cancer and the relation of the tumor invasion front and the infiltration with CD3(+) T-cells. METHODS: From a cervical squamous cell carcinoma specimen, 84 serial sections were performed and three interleaving series were stained with hematoxylin/eosin and immunohistochemistry directed against the cervical carcinoma biomarker p16(INK4a) and the T-cell marker CD3. Sections were passed through an image processing chain to obtain a reconstructed and segmented tissue volume. For local tumor invasion front analysis the mean curvature was used, which in turn was related to the respective local minimum tumor to T-cell distance as well to a T-cell originated diffusing substance's concentration at the tumor surface. RESULTS: Spatial models of the tumor tissue and the infiltrating T-cells were computed. The overall discrete compactness of the tumor invasion front was 0.89, corresponding to a pathological assessment of diffuse infiltration. The comparison of the tumor invasion front with the density of T-cell infiltration revealed an increased smoothening in regions with high T-cell infiltration. CONCLUSIONS: We could demonstrate the spatial organization of a cervical cancer and model the interaction between infiltrating T-cells with the tumor invasion front shape. Increased smoothening in regions with high T-cell infiltration suggests that T-cells may have an influence on the shaping of the tumor invasion front, e.g., by attacking tumor cells displaying specific antigens. The applied technique allows visualization of the spatial organization of tissues and could be extended to analyze multiple stains on alternating sections.

Authors: N. Wentzensen, U. D. Braumann, J. Einenkel, L. C. Horn, M. von Knebel Doeberitz, M. Loffler, J. P. Kuska

Date Published: 7th Feb 2007

Publication Type: Not specified

Human Diseases: cervical cancer

Combined SOM-portrayal of gene expression and DNA methylation landscapes disentangles modes of epigenetic regulation in glioblastoma.
GGN - German Glioma Network

Abstract (Expand)

AIM: We present here a novel method that enables unraveling the interplay between gene expression and DNA methylation in complex diseases such as cancer. MATERIALS & METHODS: The method is based … on self-organizing maps and allows for analysis of data landscapes from 'governed by methylation' to 'governed by expression'. RESULTS: We identified regulatory modules of coexpressed and comethylated genes in high-grade gliomas: two modes are governed by genes hypermethylated and underexpressed in IDH-mutated cases, while two other modes reflect immune and stromal signatures in the classical and mesenchymal subtypes. A fifth mode with proneural characteristics comprises genes of repressed and poised chromatin states active in healthy brain. Two additional modes enrich genes either in active or repressed chromatin states. CONCLUSION: The method disentangles the interplay between gene expression and methylation. It has the potential to integrate also mutation and copy number data and to apply to large sample cohorts.

Authors: L. Hopp, H. Loffler-Wirth, J. Galle, H. Binder

Date Published: 12th Jun 2018

Publication Type: Not specified

Human Diseases: glioblastoma multiforme

Combined three-dimensional microscopic visualisation of tumour-invasion front of cervical carcinoma.
ProstataCA

Abstract

Not specified

Authors: J. Einenkel, J. P. Kuska, L. C. Horn, N. Wentzensen, M. Hockel, U. D. Braumann

Date Published: 5th Aug 2006

Publication Type: Not specified

Human Diseases: cervical cancer

Commentary: Arguing for Adaptive Clinical Trials in Sepsis
SMITH - Smart Medical Information Technology for Healthcare

Abstract

Not specified

Authors: Miriam Kesselmeier, André Scherag

Date Published: 30th Oct 2018

Publication Type: Journal article

Human Diseases: disease by infectious agent

Commentary: Arguing for Adaptive Clinical Trials in Sepsis.
SMITH - Smart Medical Information Technology for Healthcare

Abstract

Not specified

Authors: M. Kesselmeier, A. Scherag

Date Published: 15th Nov 2018

Publication Type: Journal article

Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide … association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 \times 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 \times 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Authors: Antonis C. Antoniou, Christiana Kartsonaki, Olga M. Sinilnikova, Penny Soucy, Lesley McGuffog, Sue Healey, Andrew Lee, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Monica Barile, Valeria Pensotti, Barbara Pasini, Riccardo Dolcetti, Giuseppe Giannini, Anna Laura Putignano, Liliana Varesco, Paolo Radice, Phuong L. Mai, Mark H. Greene, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, Mads Thomassen, Anne-Marie Gerdes, Torben A. Kruse, Uffe Birk Jensen, Dorthe G. Crüger, Maria A. Caligo, Yael Laitman, Roni Milgrom, Bella Kaufman, Shani Paluch-Shimon, Eitan Friedman, Niklas Loman, Katja Harbst, Annika Lindblom, Brita Arver, Hans Ehrencrona, Beatrice Melin, Katherine L. Nathanson, Susan M. Domchek, Timothy Rebbeck, Ania Jakubowska, Jan Lubinski, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Bohdan Gorski, Ana Osorio, Teresa Ramón y Cajal, Florentia Fostira, Raquel Andrés, Javier Benitez, Ute Hamann, Frans B. Hogervorst, Matti A. Rookus, Maartje J. Hooning, Marcel R. Nelen, Rob B. van der Luijt, Theo A. M. van Os, Christi J. van Asperen, Peter Devilee, Hanne E. J. Meijers-Heijboer, Encarna B. Gómez Garcia, Susan Peock, Margaret Cook, Debra Frost, Radka Platte, Jean Leyland, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Diana Eccles, Kai-Ren Ong, Jackie Cook, Fiona Douglas, Joan Paterson, M. John Kennedy, Zosia Miedzybrodzka, Andrew Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Muriel Belotti, Carole Tirapo, Sylvie Mazoyer, Laure Barjhoux, Christine Lasset, Dominique Leroux, Laurence Faivre, Myriam Bronner, Fabienne Prieur, Catherine Nogues, Etienne Rouleau, Pascal Pujol, Isabelle Coupier, Marc Frénay, John L. Hopper, Mary B. Daly, Mary B. Terry, Esther M. John, Saundra S. Buys, Yosuf Yassin, Alexander Miron, David Goldgar, Christian F. Singer, Muy-Kheng Tea, Georg Pfeiler, Anne Catharina Dressler, Thomas v. O. Hansen, Lars Jønson, Bent Ejlertsen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Kenneth Offit, Marion Piedmonte, Gustavo Rodriguez, Laurie Small, John Boggess, Stephanie Blank, Jack Basil, Masoud Azodi, Amanda Ewart Toland, Marco Montagna, Silvia Tognazzo, Simona Agata, Evgeny Imyanitov, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Paul D. P. Pharoah, Lara Sucheston, Beth Y. Karlan, Christine S. Walsh, Edith Olah, Aniko Bozsik, Soo-Hwang Teo, Joyce L. Seldon, Mary S. Beattie, Elizabeth J. van Rensburg, Michelle D. Sluiter, Orland Diez, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Ina Ruehl, Raymonda Varon-Mateeva, Karin Kast, Helmut Deissler, Dieter Niederacher, Norbert Arnold, Dorothea Gadzicki, Ines Schönbuchner, Trinidad Caldes, Miguel de La Hoya, Heli Nevanlinna, Kristiina Aittomäki, Martine Dumont, Jocelyne Chiquette, Marc Tischkowitz, Xiaoqing Chen, Jonathan Beesley, Amanda B. Spurdle, Susan L. Neuhausen, Yuan Chun Ding, Zachary Fredericksen, Xianshu Wang, Vernon S. Pankratz, Fergus Couch, Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench

Date Published: 15th Aug 2011

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A … recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

Authors: Antonis C. Antoniou, Amanda B. Spurdle, Olga M. Sinilnikova, Sue Healey, Karen A. Pooley, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Wera Hofmann, Christian Sutter, Dieter Niederacher, Helmut Deissler, Trinidad Caldes, Kati Kämpjärvi, Heli Nevanlinna, Jacques Simard, Jonathan Beesley, Xiaoqing Chen, Susan L. Neuhausen, Timothy R. Rebbeck, Theresa Wagner, Henry T. Lynch, Claudine Isaacs, Jeffrey Weitzel, Patricia A. Ganz, Mary B. Daly, Gail Tomlinson, Olufunmilayo I. Olopade, Joanne L. Blum, Fergus J. Couch, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Paolo Radice, Csilla I. Szabo, Lutecia H. Mateus Pereira, Mark H. Greene, Gad Rennert, Flavio Lejbkowicz, Ofra Barnett-Griness, Irene L. Andrulis, Hilmi Ozcelik, Anne-Marie Gerdes, Maria A. Caligo, Yael Laitman, Bella Kaufman, Roni Milgrom, Eitan Friedman, Susan M. Domchek, Katherine L. Nathanson, Ana Osorio, Gemma Llort, Roger L. Milne, Javier Benítez, Ute Hamann, Frans B. L. Hogervorst, Peggy Manders, Marjolijn J. L. Ligtenberg, Ans M. W. van den Ouweland, Susan Peock, Margaret Cook, Radka Platte, D. Gareth Evans, Rosalind Eeles, Gabriella Pichert, Carol Chu, Diana Eccles, Rosemarie Davidson, Fiona Douglas, Andrew K. Godwin, Laure Barjhoux, Sylvie Mazoyer, Hagay Sobol, Violaine Bourdon, François Eisinger, Agnès Chompret, Corinne Capoulade, Brigitte Bressac-de Paillerets, Gilbert M. Lenoir, Marion Gauthier-Villars, Claude Houdayer, Dominique Stoppa-Lyonnet, Georgia Chenevix-Trench, Douglas F. Easton

Date Published: 1st Apr 2008

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations … of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 \times 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

Authors: Antonis C. Antoniou, Jonathan Beesley, Lesley McGuffog, Olga M. Sinilnikova, Sue Healey, Susan L. Neuhausen, Yuan Chun Ding, Timothy R. Rebbeck, Jeffrey N. Weitzel, Henry T. Lynch, Claudine Isaacs, Patricia A. Ganz, Gail Tomlinson, Olufunmilayo I. Olopade, Fergus J. Couch, Xianshu Wang, Noralane M. Lindor, Vernon S. Pankratz, Paolo Radice, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Monica Barile, Alessandra Viel, Anna Allavena, Valentina Dall’Olio, Paolo Peterlongo, Csilla I. Szabo, Michal Zikan, Kathleen Claes, Bruce Poppe, Lenka Foretova, Phuong L. Mai, Mark H. Greene, Gad Rennert, Flavio Lejbkowicz, Gord Glendon, Hilmi Ozcelik, Irene L. Andrulis, Mads Thomassen, Anne-Marie Gerdes, Lone Sunde, Dorthe Cruger, Uffe Birk Jensen, Maria Caligo, Eitan Friedman, Bella Kaufman, Yael Laitman, Roni Milgrom, Maya Dubrovsky, Shimrit Cohen, Ake Borg, Helena Jernström, Annika Lindblom, Johanna Rantala, Marie Stenmark-Askmalm, Beatrice Melin, Kate Nathanson, Susan Domchek, Ania Jakubowska, Jan Lubinski, Tomasz Huzarski, Ana Osorio, Adriana Lasa, Mercedes Durán, Maria-Isabel Tejada, Javier Godino, Javier Benitez, Ute Hamann, Mieke Kriege, Nicoline Hoogerbrugge, Rob B. van der Luijt, Christi J. van Asperen, Peter Devilee, E. J. Meijers-Heijboer, Marinus J. Blok, Cora M. Aalfs, Frans Hogervorst, Matti Rookus, Margaret Cook, Clare Oliver, Debra Frost, Don Conroy, D. Gareth Evans, Fiona Lalloo, Gabriella Pichert, Rosemarie Davidson, Trevor Cole, Jackie Cook, Joan Paterson, Shirley Hodgson, Patrick J. Morrison, Mary E. Porteous, Lisa Walker, M. John Kennedy, Huw Dorkins, Susan Peock, Andrew K. Godwin, Dominique Stoppa-Lyonnet, Antoine de Pauw, Sylvie Mazoyer, Valérie Bonadona, Christine Lasset, Hélène Dreyfus, Dominique Leroux, Agnès Hardouin, Pascaline Berthet, Laurence Faivre, Catherine Loustalot, Tetsuro Noguchi, Hagay Sobol, Etienne Rouleau, Catherine Nogues, Marc Frénay, Laurence Vénat-Bouvet, John L. Hopper, Mary B. Daly, Mary B. Terry, Esther M. John, Saundra S. Buys, Yosuf Yassin, Alexander Miron, David Goldgar, Christian F. Singer, Anne Catharina Dressler, Daphne Gschwantler-Kaulich, Georg Pfeiler, Thomas v. O. Hansen, Lars Jønson, Bjarni A. Agnarsson, Tomas Kirchhoff, Kenneth Offit, Vincent Devlin, Ana Dutra-Clarke, Marion Piedmonte, Gustavo C. Rodriguez, Katie Wakeley, John F. Boggess, Jack Basil, Peter E. Schwartz, Stephanie V. Blank, Amanda Ewart Toland, Marco Montagna, Cinzia Casella, Evgeny Imyanitov, Laima Tihomirova, Ignacio Blanco, Conxi Lazaro, Susan J. Ramus, Lara Sucheston, Beth Y. Karlan, Jenny Gross, Rita Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Magdalena Lochmann, Norbert Arnold, Simone Heidemann, Raymonda Varon-Mateeva, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Sabine Preisler-Adams, Karin Kast, Ines Schönbuchner, Trinidad Caldes, Miguel de La Hoya, Kristiina Aittomäki, Heli Nevanlinna, Jacques Simard, Amanda B. Spurdle, Helene Holland, Xiaoqing Chen, Radka Platte, Georgia Chenevix-Trench, Douglas F. Easton

Date Published: 6th Dec 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is …s currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 \times 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Authors: Anna Marie Mulligan, Fergus J. Couch, Daniel Barrowdale, Susan M. Domchek, Diana Eccles, Heli Nevanlinna, Susan J. Ramus, Mark Robson, Mark Sherman, Amanda B. Spurdle, Barbara Wappenschmidt, Andrew Lee, Lesley McGuffog, Sue Healey, Olga M. Sinilnikova, Ramunas Janavicius, Thomas vO Hansen, Finn C. Nielsen, Bent Ejlertsen, Ana Osorio, Iván Muñoz-Repeto, Mercedes Durán, Javier Godino, Maroulio Pertesi, Javier Benítez, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Bernardo Bonanni, Alessandra Viel, Barbara Pasini, Laura Papi, Laura Ottini, Antonella Savarese, Loris Bernard, Paolo Radice, Ute Hamann, Martijn Verheus, Hanne E. J. Meijers-Heijboer, Juul Wijnen, Encarna B. Gómez García, Marcel R. Nelen, C. Marleen Kets, Caroline Seynaeve, Madeleine M. A. Tilanus-Linthorst, Rob B. van der Luijt, Theo van Os, Matti Rookus, Debra Frost, J. Louise Jones, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Jackie Cook, Alan Donaldson, Huw Dorkins, Helen Gregory, Jacqueline Eason, Catherine Houghton, Julian Barwell, Lucy E. Side, Emma McCann, Alex Murray, Susan Peock, Andrew K. Godwin, Rita K. Schmutzler, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Ina Ruehl, Norbert Arnold, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Karin Kast, Sabine Preisler-Adams, Raymonda Varon-Mateeva, Ines Schoenbuchner, Britta Fiebig, Wolfram Heinritz, Dieter Schäfer, Heidrun Gevensleben, Virginie Caux-Moncoutier, Marion Fassy-Colcombet, François Cornelis, Sylvie Mazoyer, Mélanie Léoné, Nadia Boutry-Kryza, Agnès Hardouin, Pascaline Berthet, Danièle Muller, Jean-Pierre Fricker, Isabelle Mortemousque, Pascal Pujol, Isabelle Coupier, Marine Lebrun, Caroline Kientz, Michel Longy, Nicolas Sevenet, Dominique Stoppa-Lyonnet, Claudine Isaacs, Trinidad Caldes, Miguel de La Hoya, Tuomas Heikkinen, Kristiina Aittomäki, Ignacio Blanco, Conxi Lazaro, Rosa B. Barkardottir, Penny Soucy, Martine Dumont, Jacques Simard, Marco Montagna, Silvia Tognazzo, Emma D’Andrea, Stephen Fox, Max Yan, Tim Rebbeck, Olufunmilayo Olopade, Jeffrey N. Weitzel, Henry T. Lynch, Patricia A. Ganz, Gail E. Tomlinson, Xianshu Wang, Zachary Fredericksen, Vernon S. Pankratz, Noralane M. Lindor, Csilla Szabo, Kenneth Offit, Rita Sakr, Mia Gaudet, Jasmine Bhatia, Noah Kauff, Christian F. Singer, Muy-Kheng Tea, Daphne Gschwantler-Kaulich, Anneliese Fink-Retter, Phuong L. Mai, Mark H. Greene, Evgeny Imyanitov, Frances P. O’Malley, Hilmi Ozcelik, Gordon Glendon, Amanda E. Toland, Anne-Marie Gerdes, Mads Thomassen, Torben A. Kruse, Uffe Birk Jensen, Anne-Bine Skytte, Maria A. Caligo, Maria Soller, Karin Henriksson, von Anna Wachenfeldt, Brita Arver, Marie Stenmark-Askmalm, Per Karlsson, Yuan Chun Ding, Susan L. Neuhausen, Mary Beattie, Paul D. P. Pharoah, Kirsten B. Moysich, Katherine L. Nathanson, Beth Y. Karlan, Jenny Gross, Esther M. John, Mary B. Daly, Saundra M. Buys, Melissa C. Southey, John L. Hopper, Mary Beth Terry, Wendy Chung, Alexander F. Miron, David Goldgar, Georgia Chenevix-Trench, Douglas F. Easton, Irene L. Andrulis, Antonis C. Antoniou

Date Published: 1st Dec 2011

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND PURPOSE Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, …, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Authors: Nicola J. Armstrong, Karen A. Mather, Muralidharan Sargurupremraj, Maria J. Knol, Rainer Malik, Claudia L. Satizabal, Lisa R. Yanek, Wei Wen, Vilmundur G. Gudnason, Nicole D. Dueker, Lloyd T. Elliott, Edith Hofer, Joshua Bis, Neda Jahanshad, Shuo Li, Mark A. Logue, Michelle Luciano, Markus Scholz, Albert V. Smith, Stella Trompet, Dina Vojinovic, Rui Xia, Fidel Alfaro-Almagro, David Ames, Najaf Amin, Philippe Amouyel, Alexa S. Beiser, Henry Brodaty, Ian J. Deary, Christine Fennema-Notestine, Piyush G. Gampawar, Rebecca Gottesman, Ludovica Griffanti, Clifford R. Jack, Mark Jenkinson, Jiyang Jiang, Brian G. Kral, John B. Kwok, Leonie Lampe, David C M Liewald, Pauline Maillard, Jonathan Marchini, Mark E. Bastin, Bernard Mazoyer, Lukas Pirpamer, José Rafael Romero, Gennady V. Roshchupkin, Peter R. Schofield, Matthias L. Schroeter, David J. Stott, Anbupalam Thalamuthu, Julian Trollor, Christophe Tzourio, Jeroen van der Grond, Meike W. Vernooij, Veronica A. Witte, Margaret J. Wright, Qiong Yang, Zoe Morris, Siggi Siggurdsson, Bruce Psaty, Arno Villringer, Helena Schmidt, Asta K. Haberg, Cornelia M. van Duijn, J. Wouter Jukema, Martin Dichgans, Ralph L. Sacco, Clinton B. Wright, William S. Kremen, Lewis C. Becker, Paul M. Thompson, Thomas H. Mosley, Joanna M. Wardlaw, M. Arfan Ikram, Hieab H. H. Adams, Sudha Seshadri, Perminder S. Sachdev, Stephen M. Smith, Lenore Launer, William Longstreth, Charles DeCarli, Reinhold Schmidt, Myriam Fornage, Stephanie Debette, Paul A. Nyquist

Date Published: 1st Jul 2020

Publication Type: Journal article

Common genomic variation in the FER gene: useful to stratify patients with sepsis due to pneumonia?
LIFE - Leipzig Research Center for Civilization Diseases

Abstract

Not specified

Authors: F. Schoneweck, E. Kuhnt, M. Scholz, F. M. Brunkhorst, A. Scherag

Date Published: 30th Apr 2015

Publication Type: Not specified

Human Diseases: bacterial infectious disease, pneumonia

Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally … identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P \textless 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) \textless 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.

Authors: Xianshu Wang, V. Shane Pankratz, Zachary Fredericksen, Robert Tarrell, Mary Karaus, Lesley McGuffog, Paul D. P. Pharaoh, Bruce A. J. Ponder, Alison M. Dunning, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Claude Houdayer, Frans B. L. Hogervorst, Maartje J. Hooning, Marjolijn J. Ligtenberg, Amanda Spurdle, Georgia Chenevix-Trench, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Susan M. Domchek, Katherine L. Nathanson, Timothy R. Rebbeck, Christian F. Singer, Daphne Gschwantler-Kaulich, Catherina Dressler, Anneliese Fink, Csilla I. Szabo, Michal Zikan, Lenka Foretova, Kathleen Claes, Gilles Thomas, Robert N. Hoover, David J. Hunter, Stephen J. Chanock, Douglas F. Easton, Antonis C. Antoniou, Fergus J. Couch

Date Published: 15th Jul 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer …r have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 \times 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 \times 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 \times 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

Authors: Antonis C. Antoniou, Karoline B. Kuchenbaecker, Penny Soucy, Jonathan Beesley, Xiaoqing Chen, Lesley McGuffog, Andrew Lee, Daniel Barrowdale, Sue Healey, Olga M. Sinilnikova, Maria A. Caligo, Niklas Loman, Katja Harbst, Annika Lindblom, Brita Arver, Richard Rosenquist, Per Karlsson, Kate Nathanson, Susan Domchek, Tim Rebbeck, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Elżbieta Złowowcka-Perłowska, Ana Osorio, Mercedes Durán, Raquel Andrés, Javier Benítez, Ute Hamann, Frans B. Hogervorst, Theo A. van Os, Senno Verhoef, Hanne E. J. Meijers-Heijboer, Juul Wijnen, Encarna B. Gómez Garcia, Marjolijn J. Ligtenberg, Mieke Kriege, J. Margriet Collée, Margreet G. E. M. Ausems, Jan C. Oosterwijk, Susan Peock, Debra Frost, Steve D. Ellis, Radka Platte, Elena Fineberg, D. Gareth Evans, Fiona Lalloo, Chris Jacobs, Ros Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Jackie Cook, Joan Paterson, Fiona Douglas, Carole Brewer, Shirley Hodgson, Patrick J. Morrison, Lisa Walker, Mark T. Rogers, Alan Donaldson, Huw Dorkins, Andrew K. Godwin, Betsy Bove, Dominique Stoppa-Lyonnet, Claude Houdayer, Bruno Buecher, Antoine de Pauw, Sylvie Mazoyer, Alain Calender, Mélanie Léoné, Brigitte Bressac-de Paillerets, Olivier Caron, Hagay Sobol, Marc Frenay, Fabienne Prieur, Sandra U. Ferrer, Isabelle Mortemousque, Saundra Buys, Mary Daly, Alexander Miron, Mary U. Terry, John L. Hopper, Esther M. John, Melissa Southey, David Goldgar, Christian F. Singer, Anneliese Fink-Retter, Muy-Kheng Tea, Daphne U. Kaulich, Thomas V. Hansen, Finn C. Nielsen, Rosa B. Barkardottir, Mia Gaudet, Tomas Kirchhoff, Vijai Joseph, Ana Dutra-Clarke, Kenneth Offit, Marion Piedmonte, Judy Kirk, David Cohn, Jean Hurteau, John Byron, James Fiorica, Amanda E. Toland, Marco Montagna, Cristina Oliani, Evgeny Imyanitov, Claudine Isaacs, Laima Tihomirova, Ignacio Blanco, Conxi Lazaro, Alex Teulé, J. Del Valle, Simon A. Gayther, Kunle Odunsi, Jenny Gross, Beth Y. Karlan, Edith Olah, Soo-Hwang Teo, Patricia A. Ganz, Mary S. Beattie, Cecelia M. Dorfling, Elizabeth U. van Rensburg, Orland Diez, Ava Kwong, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Simone Heidemann, Dieter Niederacher, Sabine Preisler-Adams, Dorothea Gadzicki, Raymonda Varon-Mateeva, Helmut Deissler, Andrea Gehrig, Christian Sutter, Karin Kast, Britta Fiebig, Dieter Schäfer, Trinidad Caldes, Miguel de La Hoya, Heli Nevanlinna, Taru A. Muranen, Bernard Lespérance, Amanda B. Spurdle, Susan L. Neuhausen, Yuan C. Ding, Xianshu Wang, Zachary Fredericksen, Vernon S. Pankratz, Noralane M. Lindor, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Bernardo Bonanni, Loris Bernard, Riccardo Dolcetti, Laura Papi, Laura Ottini, Paolo Radice, Mark H. Greene, Jennifer T. Loud, Irene L. Andrulis, Hilmi Ozcelik, Anna U. Mulligan, Gord Glendon, Mads Thomassen, Anne-Marie Gerdes, Uffe B. Jensen, Anne-Bine Skytte, Torben A. Kruse, Georgia Chenevix-Trench, Fergus J. Couch, Jacques Simard, Douglas F. Easton

Date Published: 1st Feb 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored …d associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). METHODS Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. RESULTS We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 \times 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 \times 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 \times 10(-3)). CONCLUSIONS 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. IMPACT These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.

Authors: Fergus J. Couch, Mia M. Gaudet, Antonis C. Antoniou, Susan J. Ramus, Karoline B. Kuchenbaecker, Penny Soucy, Jonathan Beesley, Xiaoqing Chen, Xianshu Wang, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Sue Healey, Olga M. Sinilnikova, Irene L. Andrulis, Hilmi Ozcelik, Anna Marie Mulligan, Mads Thomassen, Anne-Marie Gerdes, Uffe Birk Jensen, Anne-Bine Skytte, Torben A. Kruse, Maria A. Caligo, Anna von Wachenfeldt, Gisela Barbany-Bustinza, Niklas Loman, Maria Soller, Hans Ehrencrona, Per Karlsson, Katherine L. Nathanson, Timothy R. Rebbeck, Susan M. Domchek, Ania Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Elzbieta Zlowocka, Tomasz Huzarski, Tomasz Byrski, Jacek Gronwald, Cezary Cybulski, Bohdan Górski, Ana Osorio, Mercedes Durán, María Isabel Tejada, Javier Benitez, Ute Hamann, Frans B. L. Hogervorst, Theo A. van Os, Flora E. van Leeuwen, Hanne E. J. Meijers-Heijboer, Juul Wijnen, Marinus J. Blok, Marleen Kets, Maartje J. Hooning, Rogier A. Oldenburg, Margreet G. E. M. Ausems, Susan Peock, Debra Frost, Steve D. Ellis, Radka Platte, Elena Fineberg, D. Gareth Evans, Chris Jacobs, Rosalind A. Eeles, Julian Adlard, Rosemarie Davidson, Diana M. Eccles, Trevor Cole, Jackie Cook, Joan Paterson, Carole Brewer, Fiona Douglas, Shirley V. Hodgson, Patrick J. Morrison, Lisa Walker, Mary E. Porteous, M. John Kennedy, Lucy E. Side, Betsy Bove, Andrew K. Godwin, Dominique Stoppa-Lyonnet, Marion Fassy-Colcombet, Laurent Castera, François Cornelis, Sylvie Mazoyer, Mélanie Léoné, Nadia Boutry-Kryza, Brigitte Bressac-de Paillerets, Olivier Caron, Pascal Pujol, Isabelle Coupier, Capucine Delnatte, Linda Akloul, Henry T. Lynch, Carrie L. Snyder, Saundra S. Buys, Mary B. Daly, Marybeth Terry, Wendy K. Chung, Esther M. John, Alexander Miron, Melissa C. Southey, John L. Hopper, David E. Goldgar, Christian F. Singer, Christine Rappaport, Muy-Kheng M. Tea, Anneliese Fink-Retter, Thomas v. O. Hansen, Finn C. Nielsen, A\dhalgeir Arason, Joseph Vijai, Sohela Shah, Kara Sarrel, Mark E. Robson, Marion Piedmonte, Kelly Phillips, Jack Basil, Wendy S. Rubinstein, John Boggess, Katie Wakeley, Amanda Ewart-Toland, Marco Montagna, Simona Agata, Evgeny N. Imyanitov, Claudine Isaacs, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Lidia Feliubadalo, Joan Brunet, Simon A. Gayther, Paul P. D. Pharoah, Kunle O. Odunsi, Beth Y. Karlan, Christine S. Walsh, Edith Olah, Soo Hwang Teo, Patricia A. Ganz, Mary S. Beattie, Elizabeth J. van Rensburg, Cecelia M. Dorfling, Orland Diez, Ava Kwong, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Simone Heidemann, Dieter Niederacher, Sabine Preisler-Adams, Dorothea Gadzicki, Raymonda Varon-Mateeva, Helmut Deissler, Andrea Gehrig, Christian Sutter, Karin Kast, Britta Fiebig, Wolfram Heinritz, Trinidad Caldes, Miguel de La Hoya, Taru A. Muranen, Heli Nevanlinna, Marc D. Tischkowitz, Amanda B. Spurdle, Susan L. Neuhausen, Yuan Chun Ding, Noralane M. Lindor, Zachary Fredericksen, V. Shane Pankratz, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Monica Barile, Loris Bernard, Alessandra Viel, Giuseppe Giannini, Liliana Varesco, Paolo Radice, Mark H. Greene, Phuong L. Mai, Douglas F. Easton, Georgia Chenevix-Trench, Kenneth Offit, Jacques Simard

Date Published: 28th Mar 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common variants in glyoxalase I do not increase chronic pancreatitis risk
Genetical Statistics and Systems Biology

Abstract (Expand)

INTRODUCTION Chronic pancreatitis (CP) may be caused by oxidative stress. An important source of reactive oxygen species (ROS) is the methylglyoxal-derived formation of advanced glycation endproducts …s (AGE). Methylglyoxal is detoxified by Glyoxalase I (GLO1). A reduction in GLO1 activity results in increased ROS. Single nucleotide polymorphisms (SNPs) of GLO1 have been linked to various inflammatory diseases. Here, we analyzed whether common GLO1 variants are associated with alcoholic (ACP) and non-alcoholic CP (NACP). METHODS Using melting curve analysis, we genotyped a screening cohort of 223 ACP, 218 NACP patients, and 328 controls for 11 tagging SNPs defined by the SNPinfo LD TAG SNP Selection tool and the functionally relevant variant rs4746. For selected variants the cohorts were extended to up to 1,441 patient samples. RESULTS In the ACP cohort, comparison of genotypes for rs1937780 between patients and controls displayed an ambiguous result in the screening cohort (p = 0.08). However, in the extended cohort of 1,441 patients no statistically significant association was found for the comparison of genotypes (p = 0.11), nor in logistic regression analysis (p = 0.214, OR 1.072, 95% CI 0.961-1.196). In the NACP screening cohort SNPs rs937662, rs1699012, and rs4746 displayed an ambiguous result when patients were compared to controls in the recessive or dominant model (p = 0.08, 0.08, and 0.07, respectively). Again, these associations were not confirmed in the extended cohorts (rs937662, dominant model: p = 0.07, logistic regression: p = 0.07, OR 1.207, 95% CI 0.985-1.480) or in the replication cohorts for rs4746 (Germany, p = 0.42, OR 1.080, 95% CI 0.673-1.124; France, p = 0.19, OR 0.90, 95% CI 0.76-1.06; China, p = 0.24, OR 1.18, 95% CI 0.90-1.54) and rs1699012 (Germany, Munich; p = 0.279, OR 0.903, 95% CI 0.750-1.087). CONCLUSIONS Common GLO1 variants do not increase chronic pancreatitis risk.

Authors: Tom Kaune, Marcus Hollenbach, Bettina Keil, Jian-Min Chen, Emmanuelle Masson, Carla Becker, Marko Damm, Claudia Ruffert, Robert Grützmann, Albrecht Hoffmeister, Rene H. M. Te Morsche, Giulia Martina Cavestro, Raffaella Alessia Zuppardo, Adrian Saftoiu, Ewa Malecka-Panas, Stanislaw Głuszek, Peter Bugert, Markus M. Lerch, Frank Ulrich Weiss, Wen-Bin Zou, Zhuan Liao, Peter Hegyi, Joost Ph Drenth, Jan Riedel, Claude Férec, Markus Scholz, Holger Kirsten, Andrea Tóth, Maren Ewers, Heiko Witt, Heidi Griesmann, Patrick Michl, Jonas Rosendahl

Date Published: 29th Oct 2019

Publication Type: Journal article

Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a … previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

Authors: Antonis C. Antoniou, Olga M. Sinilnikova, Lesley McGuffog, Sue Healey, Heli Nevanlinna, Tuomas Heikkinen, Jacques Simard, Amanda B. Spurdle, Jonathan Beesley, Xiaoqing Chen, Susan L. Neuhausen, Yuan C. Ding, Fergus J. Couch, Xianshu Wang, Zachary Fredericksen, Paolo Peterlongo, Bernard Peissel, Bernardo Bonanni, Alessandra Viel, Loris Bernard, Paolo Radice, Csilla I. Szabo, Lenka Foretova, Michal Zikan, Kathleen Claes, Mark H. Greene, Phuong L. Mai, Gad Rennert, Flavio Lejbkowicz, Irene L. Andrulis, Hilmi Ozcelik, Gord Glendon, Anne-Marie Gerdes, Mads Thomassen, Lone Sunde, Maria A. Caligo, Yael Laitman, Tair Kontorovich, Shimrit Cohen, Bella Kaufman, Efrat Dagan, Ruth Gershoni Baruch, Eitan Friedman, Katja Harbst, Gisela Barbany-Bustinza, Johanna Rantala, Hans Ehrencrona, Per Karlsson, Susan M. Domchek, Katherine L. Nathanson, Ana Osorio, Ignacio Blanco, Adriana Lasa, Javier Benítez, Ute Hamann, Frans B. L. Hogervorst, Matti A. Rookus, J. Margriet Collee, Peter Devilee, Marjolijn J. Ligtenberg, Rob B. van der Luijt, Cora M. Aalfs, Quinten Waisfisz, Juul Wijnen, Cornelis E. P. van Roozendaal, Susan Peock, Margaret Cook, Debra Frost, Clare Oliver, Radka Platte, D. Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Rosemarie Davidson, Carol Chu, Diana Eccles, Trevor Cole, Shirley Hodgson, Andrew K. Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Mélanie Léoné, Brigitte Bressac-de Paillerets, Audrey Remenieras, Olivier Caron, Gilbert M. Lenoir, Nicolas Sevenet, Michel Longy, Sandra Fert Ferrer, Fabienne Prieur, David Goldgar, Alexander Miron, Esther M. John, Saundra S. Buys, Mary B. Daly, John L. Hopper, Mary Beth Terry, Yosuf Yassin, Christian Singer, Daphne Gschwantler-Kaulich, Christine Staudigl, Thomas v. O. Hansen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Prodipto Pal, Kristi Kosarin, Kenneth Offit, Marion Piedmonte, Gustavo C. Rodriguez, Katie Wakeley, John F. Boggess, Jack Basil, Peter E. Schwartz, Stephanie V. Blank, Amanda E. Toland, Marco Montagna, Cinzia Casella, Evgeny N. Imyanitov, Anna Allavena, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Britta Fiebig, Christian Suttner, Ines Schönbuchner, Dorothea Gadzicki, Trinidad Caldes, Miguel de La Hoya, Karen A. Pooley, Douglas F. Easton, Georgia Chenevix-Trench

Date Published: 15th Nov 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common variants in the CLDN2-MORC4 and PRSS1-PRSS2 loci confer susceptibility to acute pancreatitis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND/OBJECTIVES Acute pancreatitis (AP) is one of the most common gastrointestinal disorders often requiring hospitalization. Frequent aetiologies are gallstones and alcohol abuse. In contrast …t to chronic pancreatitis (CP) few robust genetic associations have been described. Here we analysed whether common variants in the CLDN2-MORC4 and the PRSS1-PRSS2 locus that increase recurrent AP and CP risk associate with AP. METHODS We screened 1462 AP patients and 3999 controls with melting curve analysis for SNPs rs10273639 (PRSS1-PRSS2), rs7057398 (RIPPLY), and rs12688220 (MORC4). Calculations were performed for the overall group, aetiology, and gender sub-groups. To examine genotype-phenotype relationships we performed several meta-analyses. RESULTS Meta-analyses of all AP patients depicted significant (p-value \textless 0.05) associations for rs10273639 (odds ratio (OR) 0.88, 95% confidence interval (CI) 0.81-0.97, p-value 0.01), rs7057398 (OR 1.27, 95% CI 1.07-1.5, p-value 0.005), and rs12688220 (OR 1.32, 95% CI 1.12-1.56, p-value 0.001). For the different aetiology groups a significant association was shown for rs10273639 (OR 0.76, 95% CI 0.63-0.92, p-value 0.005), rs7057398 (OR 1.43, 95% CI 1.07-1.92, p-value 0.02), and rs12688220 (OR 1.44, 95% CI 1.07-1.93, p-value 0.02) in the alcoholic sub-group only. CONCLUSIONS The association of CP risk variants with different AP aetiologies, which is strongest in the alcoholic AP group, might implicate common pathomechanisms most likely between alcoholic AP and CP.

Authors: Frank Ulrich Weiss, Nico Hesselbarth, Andrea Párniczky, Dora Mosztbacher, Felix Lämmerhirt, Claudia Ruffert, Peter Kovacs, Sebastian Beer, Katharina Seltsam, Heidi Griesmann, Richard Böhme, Tom Kaune, Marcus Hollenbach, Hans-Ulrich Schulz, Peter Simon, Julia Mayerle, Markus M. Lerch, Giulia Martina Cavestro, Raffaella Alessia Zuppardo, Milena Di Leo, Pier Alberto Testoni, Ewa Malecka-Panas, Anita Gasirowska, Stanislaw Głuszek, Peter Bugert, Andrea Szentesi, Joachim Mössner, Heiko Witt, Patrick Michl, Peter Hégyi, Markus Scholz, Jonas Rosendahl

Date Published: 1st Jul 2018

Publication Type: Journal article

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Mutations in the BRCA1 gene substantially increase a woman’s lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers … identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Authors: David G. Cox, Jacques Simard, Daniel Sinnett, Yosr Hamdi, Penny Soucy, Manon Ouimet, Laure Barjhoux, Carole Verny-Pierre, Lesley McGuffog, Sue Healey, Csilla Szabo, Mark H. Greene, Phuong L. Mai, Irene L. Andrulis, Mads Thomassen, Anne-Marie Gerdes, Maria A. Caligo, Eitan Friedman, Yael Laitman, Bella Kaufman, Shani S. Paluch, Åke Borg, Per Karlsson, Marie Stenmark Askmalm, Gisela Barbany Bustinza, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Javier Benítez, Ute Hamann, Matti A. Rookus, Ans M. W. van den Ouweland, Margreet G. E. M. Ausems, Cora M. Aalfs, Christi J. van Asperen, Peter Devilee, Hans J. J. P. Gille, Susan Peock, Debra Frost, D. Gareth Evans, Ros Eeles, Louise Izatt, Julian Adlard, Joan Paterson, Jacqueline Eason, Andrew K. Godwin, Marie-Alice Remon, Virginie Moncoutier, Marion Gauthier-Villars, Christine Lasset, Sophie Giraud, Agnès Hardouin, Pascaline Berthet, Hagay Sobol, François Eisinger, Brigitte Bressac de Paillerets, Olivier Caron, Capucine Delnatte, David Goldgar, Alex Miron, Hilmi Ozcelik, Saundra Buys, Melissa C. Southey, Mary Beth Terry, Christian F. Singer, Anne-Catharina Dressler, Muy-Kheng Tea, Thomas v. O. Hansen, Oskar Johannsson, Marion Piedmonte, Gustavo C. Rodriguez, Jack B. Basil, Stephanie Blank, Amanda E. Toland, Marco Montagna, Claudine Isaacs, Ignacio Blanco, Simon A. Gayther, Kirsten B. Moysich, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Christian Sutter, Dorothea Gadzicki, Britta Fiebig, Trinidad Caldes, Rachel Laframboise, Heli Nevanlinna, Xiaoqing Chen, Jonathan Beesley, Amanda B. Spurdle, Susan L. Neuhausen, Yuan C. Ding, Fergus J. Couch, Xianshu Wang, Paolo Peterlongo, Siranoush Manoukian, Loris Bernard, Paolo Radice, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Olga M. Sinilnikova

Date Published: 1st Dec 2011

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Communication Architecture for AAL: Supporting Patient Care by Health Care Providers in AAL-enhanced Living Quarters
Management of health information systems

Abstract

Not specified

Authors: T. Nitzsche, S. Thiele, A. Häber, Alfred Winter

Date Published: 20th Jan 2018

Publication Type: Journal article

Communication Support for Managed Care
Management of health information systems

Abstract

Not specified

Authors: Ulrike Müller, Gert Funkat, Dirk Jaeckel, André Kaeding, Alfred Winter

Date Published: 2005

Publication Type: Journal article

Comparative evaluation of automated information extraction from pathology reports in three German cancer registries
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

Feeding cancer registries with data extracted from textual reports, while maintaining a high level of data quality, has always been a labour-intensive task, due to the heterogeneity of the sources. The … support of this task by IT solutions is expected to accelerate and optimise this process. To this end, the commercial text mining system Averbis Health Discovery was tailored to extract information from free text at the cancer registry of the federal state of Baden-Württemberg. The following entity types were extracted from German-language pathology reports: tumour localisation and morphology, pTNM, grading, (sentinel) nodes examined and affected, laterality and R-class. According to the entity type, several machine learning approaches as well as rules were used for the tumour types breast, prostate, colorectal and skin. Whereas for the pilot site, F values ranged between 0.800 and 0.996, values dropped when applying the extraction pipeline to two new sites (cancer registries Rhineland-Palatinate and Lower Saxony), for morphology from 0.950 to 0.657 and 0.933, and for localisation (topography) from 0.902 to 0.675 and 0.768. There was much less difference with R-class and lymph node counts. A thorough error analysis revealed numerous issues that explain these differences, such as different workflows between the sites, disagreements between textual and coded content as well as different handlings of missing values.

Authors: Stefan Schulz, Sonja Fix, Peter Klügl, Tamira Bachmayer, Tobias Hartz, Martin Richter, Nils Herm-Stapelberg, Philipp Daumke

Date Published: 2021

Publication Type: Journal article

Comparing a Japanese and a German Hospital Information System - Assessing Structural Quality by 3LGM^2 Models
Management of health information systems

Abstract

Not specified

Authors: Franziska Jahn, Lutz Ißler, Alfred Winter, Katsuhiko Takabayashi

Date Published: 2009

Publication Type: Journal article

Comparing measures of association in 2x2 probability tables
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Dirk Hasenclever, Markus Scholz

Date Published: 2013

Publication Type: Journal article

Comparing Measures of Association in 2x2 Probability Tables
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Dirk Hasenclever, Markus Scholz

Date Published: 23rd Aug 2016

Publication Type: Journal article

Comparing performance of modern genotype imputation methods in different ethnicities
Genetical Statistics and Systems Biology

Abstract (Expand)

A variety of modern software packages are available for genotype imputation relying on advanced concepts such as pre-phasing of the target dataset or utilization of admixed reference panels. In this … study, we performed a comprehensive evaluation of the accuracy of modern imputation methods on the basis of the publicly available POPRES samples. Good quality genotypes were masked and re-imputed by different imputation frameworks: namely MaCH, IMPUTE2, MaCH-Minimac, SHAPEIT-IMPUTE2 and MaCH-Admix. Results were compared to evaluate the relative merit of pre-phasing and the usage of admixed references. We showed that the pre-phasing framework SHAPEIT-IMPUTE2 can overestimate the certainty of genotype distributions resulting in the lowest percentage of correctly imputed genotypes in our case. MaCH-Minimac performed better than SHAPEIT-IMPUTE2. Pre-phasing always reduced imputation accuracy. IMPUTE2 and MaCH-Admix, both relying on admixed-reference panels, showed comparable results. MaCH showed superior results if well-matched references were available (Nei’s GST ≤ 0.010). For small to medium datasets, frameworks using genetically closest reference panel are recommended if the genetic distance between target and reference data set is small. Our results are valid for small to medium data sets. As shown on a larger data set of population based German samples, the disadvantage of pre-phasing decreases for larger sample sizes.

Authors: Nab Raj Roshyara, Katrin Horn, Holger Kirsten, Peter Ahnert, Markus Scholz

Date Published: 1st Dec 2016

Publication Type: Journal article

Comparison and modelling of pegylated or unpegylated G-CSF schedules in CHOP-14 regimen of elderly patients with aggressive B-cell lymphoma.
GLA - German Lymphoma Alliance, Genetical Statistics and Systems Biology

Abstract (Expand)

Bi-weekly (R)-CHOP therapy is one of the standard treatmentS for elderly patients with aggressive B-cell lymphoma, but it is only feasible with supportive G-CSF treatment. In the trials of the DSHNHL, … either unpegylated G-CSF was given daily over 7 or 10 days or pegylated G-CSF was applied at day 4 of each cycle. These schedules were planned on the basis of simulations of a biomathematical pharmacokinetic/pharmacodynamic model. By analysing the observed data, we investigated whether our model predictions were correct and whether even better schedules can be proposed. We used data on 249 matched patients of two prospective trials, RICOVER-60 and PEGFILGRASTIM. The three G-CSF-schedules showed similar outcomes regarding leukocytopenia, infections and days in hospital, with pegylated G-CSF having slightly but not significantly better scores in all three endpoints. Regarding pegylated G-CSF, the best timing is predicted to be any day between days 4 and 7. With respect to unpegylated G-CSF, the starting day is less important, but it should be continued until the end of each cycle.The three G-CSF-schedules are interchangeable in (R)-CHOP-14 for elderly patients with aggressive B-cell lymphoma. Our model correctly predicts time courses of leukocytes. Further model predictions are presented, which can be tested in subsequent clinical trials.

Authors: S. Zeynalova, M. Ziepert, M. Scholz, S. Schirm, C. Zwick, M. Pfreundschuh, M. Loeffler

Date Published: 30th Jul 2013

Publication Type: Not specified

Human Diseases: B-cell lymphoma

Comparison between German and Japanese Hospital Information Systems by 3LGM2 analysis
Management of health information systems

Abstract

Not specified

Authors: Franziska Jahn, Katsuhiko Takabayashi, Takahiro Suzuki, Shinsuke Fujita, Alfred Winter

Date Published: 2007

Publication Type: InCollection

Comparison of estimators for measures of linkage disequilibrium
Genetical Statistics and Systems Biology

Abstract (Expand)

The measurement of biallelic pair-wise association called linkage disequilibrium (LD) is an important issue in order to understand the genomic architecture. A plethora of measures of association in two … by two tables have been proposed in the literature. Beside the problem of choosing an appropriate measure, the problem of their estimation has been neglected in the literature. It needs to be emphasized that the definition of a measure and the choice of an estimator function for it are conceptually unrelated tasks. In this paper, we compare the performance of various estimators for the three popular LD measures D’, r and Y in a simulation study for small to moderate samples sizes (N\textless=500). The usual frequency-plug-in estimators can lead to unreliable or undefined estimates. Estimators based on the computationally expensive volume measures have been proposed recently as a remedy to this well-known problem. We confirm that volume estimators have better expected mean square error than the naive plug-in estimators. But they are outperformed by estimators plugging-in easy to calculate non-informative Bayesian probability estimates into the theoretical formulae for the measures. Fully Bayesian estimators with non-informative Dirichlet priors have comparable accuracy but are computationally more expensive. We recommend the use of non-informative Bayesian plug-in estimators based on Jeffreys’ prior, in particular when dealing with SNP array data where the occurrence of small table entries and table margins is likely.

Authors: Markus Scholz, Dirk Hasenclever

Date Published: 2010

Publication Type: Journal article

Comparison of scoring methods for the detection of causal genes with or without rare variants
Genetical Statistics and Systems Biology

Abstract (Expand)

Rare causal variants are believed to significantly contribute to the genetic basis of common diseases or quantitative traits. Appropriate statistical methods are required to discover the highest possible … number of disease-relevant variants in a genome-wide screening study. The publicly available Genetic Analysis Workshop 17 data set consists of 697 individuals and 24,487 genetic variants. It includes a simulated complex disease model with intermediate quantitative phenotypes. We compare four gene-wise scoring methods with respect to ranking of causal genes under variable allele frequency thresholds for collapsing of rare variants and considering whether or not rare variants were included. We also compare causal genes for which the ranks differ clearly between scoring methods regarding such characteristics as number and strength of causal variants. We corroborated our findings with additional simulations. We found that the maximum statistics method was superior in assigning high ranks to genes with a single strong causal variant. Hotelling’s T2 test was superior for genes with several independent causal variants. This was consistent for all phenotypes and was confirmed by single-gene analyses and additional simulations. The multivariate analysis performed similarly to Hotelling’s T2 test. The least absolute shrinkage and selection operator (LASSO) analysis was widely comparable with the maximum statistics method. We conclude that the maximum statistics method is a superior alternative to Hotelling’s T2 test if one expects only one independent causal variant per gene with a dominating effect. Such a variant could also be a supermarker derived by collapsing rare variants. Because the true nature of the genetic effect is unknown for real data, both methods need to be taken into consideration.

Authors: Markus Scholz, Holger Kirsten

Date Published: 1st Dec 2011

Publication Type: Journal article

Complexin2 modulates working memory-related neural activity in patients with schizophrenia
Genetical Statistics and Systems Biology

Abstract (Expand)

The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight … into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associated with cognitive dysfunction in schizophrenia patients. Similarly, cognitive functioning was found to be impaired in Cplx2 gene-deficient mice if they were subjected to maternal deprivation or mild brain trauma during puberty. Here, we aimed to study seven common CPLX2 single-nucleotide polymorphisms (SNPs) and their neurogenetic risk mechanisms by investigating their relationship to a schizophrenia-related functional neuroimaging intermediate phenotype. We examined functional MRI and genotype data collected from 104 patients with DSM-IV-diagnosed schizophrenia and 122 healthy controls who participated in the Mind Clinical Imaging Consortium study of schizophrenia. Seven SNPs distributed over the whole CPLX2 gene were tested for association with working memory-elicited neural activity in a frontoparietal neural network. Three CPLX2 SNPs were significantly associated with increased neural activity in the dorsolateral prefrontal cortex and intraparietal sulcus in the schizophrenia sample, but showed no association in healthy controls. Since increased working memory-related neural activity in individuals with or at risk for schizophrenia has been interpreted as ’neural inefficiency,’ these findings suggest that certain variants of CPLX2 may contribute to impaired brain function in schizophrenia, possibly combined with other deleterious genetic variants, adverse environmental events, or developmental insults.   The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associated with cognitive dysfunction in schizophrenia patients. Similarly, cognitive functioning was found to be impaired in Cplx2 gene-deficient mice if they were subjected to maternal deprivation or mild brain trauma during puberty. Here, we aimed to study seven common CPLX2 single-nucleotide polymorphisms (SNPs) and their neurogenetic risk mechanisms by investigating their relationship to a schizophrenia-related functional neuroimaging intermediate phenotype. We examined functional MRI and genotype data collected from 104 patients with DSM-IV-diagnosed schizophrenia and 122 healthy controls who participated in the Mind Clinical Imaging Consortium study of schizophrenia. Seven SNPs distributed over the whole CPLX2 gene were tested for association with working memory-elicited neural activity in a frontoparietal neural network. Three CPLX2 SNPs were significantly associated with increased neural activity in the dorsolateral prefrontal cortex and intraparietal sulcus in the schizophrenia sample, but showed no association in healthy controls. Since increased working memory-related neural activity in individuals with or at risk for schizophrenia has been interpreted as ’neural inefficiency,’ these findings suggest that certain variants of CPLX2 may contribute to impaired brain function in schizophrenia, possibly combined with other deleterious genetic variants, adverse environmental events, or developmental insults.   The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associated with cognitive dysfunction in schizophrenia patients. Similarly, cognitive functioning was found to be impaired in Cplx2 gene-deficient mice if they were subjected to maternal deprivation or mild brain trauma during puberty. Here, we aimed to study seven common CPLX2 single-nucleotide polymorphisms (SNPs) and their neurogenetic risk mechanisms by investigating their relationship to a schizophrenia-related functional neuroimaging intermediate phenotype. We examined functional MRI and genotype data collected from 104 patients with DSM-IV-diagnosed schizophrenia and 122 healthy controls who participated in the Mind Clinical Imaging Consortium study of schizophrenia. Seven SNPs distributed over the whole CPLX2 gene were tested for association with working memory-elicited neural activity in a frontoparietal neural network. Three CPLX2 SNPs were significantly associated with increased neural activity in the dorsolateral prefrontal cortex and intraparietal sulcus in the schizophrenia sample, but showed no association in healthy controls. Since increased working memory-related neural activity in individuals with or at risk for schizophrenia has been interpreted as ’neural inefficiency,’ these findings suggest that certain variants of CPLX2 may contribute to impaired brain function in schizophrenia, possibly combined with other deleterious genetic variants, adverse environmental events, or developmental insults. //  The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associated with cognitive dysfunction in schizophrenia patients. Similarly, cognitive functioning was found to be impaired in Cplx2 gene-deficient mice if they were subjected to maternal deprivation or mild brain trauma during puberty. Here, we aimed to study seven common CPLX2 single-nucleotide polymorphisms (SNPs) and their neurogenetic risk mechanisms by investigating their relationship to a schizophrenia-related functional neuroimaging intermediate phenotype. We examined functional MRI and genotype data collected from 104 patients with DSM-IV-diagnosed schizophrenia and 122 healthy controls who participated in the Mind Clinical Imaging Consortium study of schizophrenia. Seven SNPs distributed over the whole CPLX2 gene were tested for association with working memory-elicited neural activity in a frontoparietal neural network. Three CPLX2 SNPs were significantly associated with increased neural activity in the dorsolateral prefrontal cortex and intraparietal sulcus in the schizophrenia sample, but showed no association in healthy controls. Since increased working memory-related neural activity in individuals with or at risk for schizophrenia has been interpreted as ’neural inefficiency,’ these findings suggest that certain variants of CPLX2 may contribute to impaired brain function in schizophrenia, possibly combined with other deleterious genetic variants, adverse environmental events, or developmental insults.

Authors: Johanna Hass, Esther Walton, Holger Kirsten, Jessica Turner, Rick Wolthusen, Veit Roessner, Scott R. Sponheim, Daphne Holt, Randy Gollub, Vince D. Calhoun, Stefan Ehrlich

Date Published: 1st Mar 2015

Publication Type: Journal article

Components of a Mediterranean diet and their impact on cognitive functions in aging.
LIFE Adult

Abstract (Expand)

BACKGROUND: Adhering to the Mediterranean diet (MeDi) is known to be beneficial with regard to many age-associated diseases including cardiovascular diseases and type 2 diabetes. Recent studies also … suggest an impact on cognition and brain structure, and increasing effort is made to track effects down to single nutrients. AIMS: We aimed to review whether two MeDi components, i.e., long-chain omega-3 fatty acids (LC-n3-FA) derived from sea-fish, and plant polyphenols including resveratrol (RSV), exert positive effects on brain health in aging. CONTENT: We summarized health benefits associated with the MeDi and evaluated available studies on the effect of (1) fish-consumption and LC-n3-FA supplementation as well as (2) diet-derived or supplementary polyphenols such as RSV, on cognitive performance and brain structure in animal models and human studies. Also, we discussed possible underlying mechanisms. CONCLUSION: A majority of available studies suggest that consumption of LC-n3-FA with fish or fishoil-supplements exerts positive effects on brain health and cognition in older humans. However, more large-scale randomized controlled trials are needed to draw definite recommendations. Considering polyphenols and RSV, only few controlled studies are available to date, yet the evidence based on animal research and first interventional human trials is promising and warrants further investigation. In addition, the concept of food synergy within the MeDi encourages future trials that evaluate the impact of comprehensive lifestyle patterns to help maintaining cognitive functions into old age.

Authors: S. Huhn, S. Kharabian Masouleh, M. Stumvoll, A. Villringer, A. V. Witte

Date Published: 29th Jul 2015

Publication Type: Not specified

Human Diseases: cardiovascular system disease, diabetes mellitus

Comprehensive cytogenetic characterization of an esthesioneuroblastoma
Genetical Statistics and Systems Biology

Abstract (Expand)

Esthesioneuroblastoma is a malignant neuroectodermal tumor originating from olfactory epithelial cells in the nasal vault. Due to the rarity of this tumor entity, cytogenetic data are very limited. … Therefore, we performed comprehensive cytogenetic analyses of an esthesioneuroblastoma, Hyam’s grade III-IV, using trypsin-Giemsa staining (GTG banding), multicolor fluorescence in situ hybridization (M-FISH), and locus-specific FISH complemented by molecular karyotyping using high-density single nucleotide polymorphism arrays. GTG banding of 25 metaphases revealed 54 structural intrachromosomal aberrations, predominantly located on 2q, 6q, 21q, and 22q, which were confirmed by FISH analysis. Interestingly, we found two novel, so far not described deletions, del(2)(q37) and del(21)(q22). Using GTG banding, locus-specific FISH, and M-FISH, we detected numeric changes of chromosomes 5, 17, 19, and 22, as well as trisomy 8 at low frequency. Applying SNP array karyotyping, we confirmed the chromosomal aberrations del(2)(q37.3), del(3)(q27.2), del(10)(q26.11), chromosomal imbalance on 17q, del(21)(q22), and revealed a number of so far unknown aberrations (gain of 2q14.3, 13q33.3, and 13q34). While the cytogenetically revealed low frequency mosaic del(6)(q22q24) was not visible using SNP array karyotyping, some of the smaller imbalances (SNP array data) could not have been detected by classic cytogenetic analysis. Therefore, our study supports the usefulness of applying complementary methods for cytogenetic analysis.

Authors: Heidrun Holland, Ronald Koschny, Wolfgang Krupp, Jürgen Meixensberger, Manfred Bauer, Holger Kirsten, Peter Ahnert

Date Published: 1st Mar 2007

Publication Type: Journal article

Comprehensive high-resolution genomic profiling and cytogenetics of human chondrocyte cultures by GTG-banding, locus-specific FISH, SKY and SNP array
Genetical Statistics and Systems Biology

Abstract (Expand)

In the development of cell-based medicinal products, it is crucial to guarantee that the application of such an advanced therapy medicinal product (ATMP) is safe for the patients. The consensus of the … European regulatory authorities is: \textquotedblIn conclusion, on the basis of the state of art, conventional karyotyping can be considered a valuable and useful technique to analyse chromosomal stability during preclinical studies\textquotedbl. 408 chondrocyte samples (84 monolayers and 324 spheroids) from six patients were analysed using trypsin-Giemsa staining, spectral karyotyping and fluorescence in situ hybridisation, to evaluate the genetic stability of chondrocyte samples from non-clinical studies. Single nucleotide polymorphism (SNP) array analysis was performed on chondrocyte spheroids from five of the six donors. Applying this combination of techniques, the genetic analyses performed revealed no significant genetic instability until passage 3 in monolayer cells and interphase cells from spheroid cultures at different time points. Clonal occurrence of polyploid metaphases and endoreduplications were identified associated with prolonged cultivation time. Also, gonosomal losses were observed in chondrocyte spheroids, with increasing passage and duration of the differentiation phase. Interestingly, in one of the donors, chromosomal aberrations that are also described in extraskeletal myxoid chondrosarcoma were identified. The SNP array analysis exhibited chromosomal aberrations in two donors and copy neutral losses of heterozygosity regions in four donors. This study showed the necessity of combined genetic analyses at defined cultivation time points in quality studies within the field of cell therapy.

Authors: M. Wallenborn, O. Petters, D. Rudolf, H. Hantmann, M. Richter, P. Ahnert, L. Rohani, J. J. Smink, G. C. Bulwin, W. Krupp, R. M. Schulz, H. Holland

Date Published: 23rd Mar 2018

Publication Type: Journal article

Comprehensive high-resolution genomic profiling and cytogenetics of two pediatric and one adult medulloblastoma
Genetical Statistics and Systems Biology

Abstract (Expand)

Medulloblastoma (WHO grade IV) is a rare, malignant, invasive, embryonal tumor which mainly occurs in children and represents less than 1% of all adult brain tumors. Systematic comprehensive genetic … analyses on medulloblastomas are rare but necessary to provide more detailed information. Therefore, we performed comprehensive cytogenetic analyses (blood and tissue) of two pediatric and one adult medulloblastoma, using trypsin-Giemsa staining, spectral karyotyping (tissues only), SNP-arrays, and gene expression analyses. We confirmed frequently detected chromosomal aberrations in medulloblastoma, such as +7q, -8p/q, -9q, -11q, -12q, and +17q and identified novel genetic events. Applying SNP-array, we identified constitutional de novo losses 5q21.1, 15q11.2, 17q21.31, 19p12 (pediatric medulloblastoma), 9p21.1, 19p12, 19q13.3, 21q11.2 (adult medulloblastoma) and gains 16p11.1-16p11.2, 18p11.32, Yq11.223-Yq11.23 (pediatric medulloblastoma), Xp22.31 (adult medulloblastoma) possibly representing inherited causal events for medulloblastoma formation. We show evidence for somatic segmental uniparental disomy in regions 1p36, 6q16.3, 6q24.1, 14q21.2, 17p13.3, and 17q22 not previously described for primary medulloblastoma. Gene expression analysis supported classification of the adult medulloblastoma to the WNT-subgroup and classification of pediatric medulloblastomas to group 3 tumors. Analyses of tumors and matched normal tissues (blood) with a combination of complementary techniques will help to further elucidate potentially causal genetic events for medulloblastomas.

Authors: Heidrun Holland, Li-Xin Xu, Peter Ahnert, Holger Kirsten, Ronald Koschny, Manfred Bauer, Ralf Schober, Jürgen Meixensberger, Wolfgang Krupp

Date Published: 1st Sep 2013

Publication Type: Journal article

Compression of dementia morbidity by higher education
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Objectives: The concept of compression of morbidity suggests that compressing cognitive morbidity into a shorter lifetime period would result in a better cumulative lifetime cognitive functioning. Some … lifestyle factors, like higher education, that are known to protect cognitive functioning in old age and lower dementia risk, could compress cognitive morbidity. Therefore the aim of our study was to investigate whether higher education leads to a better cumulative lifetime cognitive functioning and, hence, the compression of cognitive morbidity. Methods: Data were derived from the population-based Leipzig longitudinal study of the aged (LEILA75+). From 1998-2005, individuals aged 75 years and older underwent up to seven assessments at a 1.5-year interval and a long-term follow-up assessment after 15 years (2013). Analyses on the impact of higher education on compression of cognitive morbidity were carried out via multilevel logistic mixed-models and tobit analyses using the participants’ age as time scale (n=742). Results: The results revealed that more years of education were significantly associated with a better cognitive functioning but not with the age at dementia onset or the age at death. Computation of cumulative lifetime cognitive functioning was weighted for survival probability and indicated a gain of 21 MMSE points during the lifetime period 75 through 100 years of age by having more than 12 years of education compared to having less than 9 years of education. Conclusion: Overall, the findings suggest a compression of cognitive morbidity by higher education prior to dementia onset. More years of education could therefore contribute to a better cognitive functioning even under consideration of survival probability. Hence, efforts to ensure access to higher education for as many people in a population as possible might compress disease burden due to cognitive morbidity.

Authors: F. S. Then, T. Luck, H. Matschinger, M. C. Angermeyer, S. G. Riedel-Heller

Date Published: 1st Mar 2016

Publication Type: Not specified

Human Diseases: dementia

Concept and implementation of data usage proposal process based on international standards in SMITH
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

Accessing secondary-use healthcare data in Germany requires contracting with each organization that acts as a data provider. The SMITH Service Platform offers a central access point for scientists, … facilitating contracting as part of an integrated data use and access process with several Data Integration Centers (DIC) at once. Process support is realized by a central Business Process Engine (BPE), which manages process definition and process control, combined with a central IHE infrastructure. The use of IHE XDS and IHE XDW profiles enables the exchange of process instance information with multiple distributed visualization and user interaction tools for provided user tasks based on international standards. User task information include structured forms for submitting instructions and results as task input and output for the users, and are synchronized between the shared process instance and the BPE. A reference user interface is also provided with the SMITH Marketplace. In the future, further standardization efforts regarding the structured forms and the use of the IHE XDW profile should be pursued.

Authors: Marcel Klötgen, Eric Fiege, Salima Houta

Date Published: 1st May 2021

Publication Type: InCollection

Conceptualizing neuropsychiatric diseases with multimodal data-driven meta-analyses - the case of behavioral variant frontotemporal dementia.
LIFE Adult

Abstract (Expand)

INTRODUCTION: Uniform coordinate systems in neuroimaging research have enabled comprehensive systematic and quantitative meta-analyses. Such approaches are particularly relevant for neuropsychiatric … diseases, the understanding of their symptoms, prediction and treatment. Behavioral variant frontotemporal dementia (bvFTD), a common neurodegenerative syndrome, is characterized by deep alterations in behavior and personality. Investigating this 'nexopathy' elucidates the healthy social and emotional brain. METHODS: Here, we combine three multimodal meta-analyses approaches - anatomical and activation likelihood estimates and behavioral domain profiles - to identify neural correlates of bvFTD in 417 patients and 406 control subjects and to extract mental functions associated with this disease by meta-analyzing functional activation studies in the comprehensive probabilistic functional brain atlas of the BrainMap database. RESULTS: The analyses identify the frontomedian cortex, basal ganglia, anterior insulae and thalamus as most relevant hubs, with a regional dissociation between atrophy and hypometabolism. Neural networks affected by bvFTD were associated with emotion and reward processing, empathy and executive functions (mainly inhibition), suggesting these functions as core domains affected by the disease and finally leading to its clinical symptoms. In contrast, changes in theory of mind or mentalizing abilities seem to be secondary phenomena of executive dysfunctions. CONCLUSIONS: The study creates a novel conceptual framework to understand neuropsychiatric diseases by powerful data-driven meta-analytic approaches that shall be extended to the whole neuropsychiatric spectrum in the future.

Authors: M. L. Schroeter, A. R. Laird, C. Chwiesko, C. Deuschl, E. Schneider, D. Bzdok, S. B. Eickhoff, J. Neumann

Date Published: 26th Apr 2014

Publication Type: Not specified

Human Diseases: frontotemporal dementia

Consolidation radiotherapy to bulky disease in aggressive NHL. First results of the NHL B-94 trial of the DSHNHL.
GLA - German Lymphoma Alliance

Abstract (Expand)

The impact of radiotherapy in aggressive NHL is not well defined. In the NHL B-94 trial of the DSHNHL, an irradiation of bulky disease areas was done after completing 6 cycles of CHOP/CHOEP chemotherapy. … In the entire patient group, including those patients with extranodal disease and those who did not receive the complete chemotherapy, bulky disease was a significant independent prognostic factor concerning recurrence-free survival (66.1% (no bulk) vs. 53.3% (bulk), p=0.0001). Out of 366 patients with nodal disease only and 6 cycles of chemotherapy according to the protocol, 84 of 91 patients with bulky disease were irradiated with 36 Gy. In this group of patients the prognostic impact of bulky disease could not be shown any longer (recurrence-free survival 77.3% (no bulk) vs. 74.1% (bulk). Localized radiotherapy of bulky disease areas may therefore have contributed to an improvement in outcome in this high-risk group.

Authors: C. Rube, T. P. Nguyen, M. Kloss, M. Loeffler, L. Trumper, M. Pfreunschuh

Date Published: 5th Jan 2002

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

Continouus Annotation Quality Control, Support for Hierarchically Structured Label Sets and Long-Segment Annotation with WAT-SL 2.0
SMITH - Smart Medical Information Technology for Healthcare

Abstract

Not specified

Authors: Matthias Löbe, O. Beyan, Sebastian Stäubert, Frank A. Meineke, D. Ammon, Alfred Winter, S. Deckert, Markus Löffler, Toralf Kirsten

Date Published: 2019

Publication Type: InProceedings

Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

PURPOSE To estimate the risk for contralateral breast cancer in members of BRCA1- and BRCA2-positive families and to determine predictive risk factors. PATIENTS AND METHODS A retrospective, multicenter, …er, cohort study was performed from 1996 until 2008 and comprised 2,020 women with unilateral breast cancer (index patients, n = 978; relatives, n = 1.42) from 978 families who had a BRCA1 or BRCA2 mutation. Cox regression analysis was applied to assess the association of age at first breast cancer with time from first to contralateral breast cancer, stratified by the affected BRCA gene. RESULTS The cumulative risk for contralateral breast cancer 25 years after first breast cancer was 47.4% (95% CI, 38.8% to 56.0%) for patients from families with BRCA1 or BRCA2 mutations. Members of families with BRCA1 mutations had a 1.6-fold (95% CI, 1.2-fold to 2.3-fold) higher risk of contralateral breast cancer than members of families with BRCA2 mutations. Younger age at first breast cancer was associated with a significantly higher risk of contralateral breast cancer in patients with BRCA1 mutation, and a trend was observed in patients with BRCA2 mutation. After 25 years, 62.9% (95% CI, 50.4% to 75.4%) of patients with BRCA1 mutation who were younger than 40 years of age at first breast cancer developed contralateral breast cancer, compared with only 19.6% (95% CI, 5.3% to 33.9%) of those who were older than 50 years of age at first breast cancer. CONCLUSION Contralateral breast cancer risk depends on age at first breast cancer and on the affected BRCA gene, and this risk should be considered in treatment planning.

Authors: Monika K. Graeser, Christoph Engel, Kerstin Rhiem, Dorothea Gadzicki, Ulrich Bick, Karin Kast, Ursula G. Froster, Bettina Schlehe, Astrid Bechtold, Norbert Arnold, Sabine Preisler-Adams, Carolin Nestle-Kraemling, Mohammad Zaino, Markus Loeffler, Marion Kiechle, Alfons Meindl, Dominic Varga, Rita K. Schmutzler

Date Published: 10th Dec 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1).
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: High-dose therapy (HDT) followed by transplantation of autologous haemopoietic stem cells is frequently done as part of first-line therapy in young patients with high-risk aggressive B-cell … lymphoma. We investigated whether HDT with cytotoxic agents identical to those used for conventional therapy followed by autologous stem-cell transplantation (ASCT) improved survival outcome compared with conventional chemotherapy when rituximab was added to both modalities. METHODS: We did an open-label, randomised trial comparing conventional chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) and rituximab (R-CHOEP-14) with dose-escalated sequential HDT and rituximab (R-MegaCHOEP) followed by repetitive ASCT in high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) patients aged 18-60 years with aggressive B-cell lymphoma. Eligible patients received radiotherapy for bulky, extranodal disease, or both. Randomisation (1:1) used the Pocock minimisation algorithm; patients were stratified by age-adjusted IPI factors, bulky disease, and centre. The primary endpoint was event-free survival. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00129090. FINDINGS: 136 patients were randomly assigned to R-CHOEP-14 and 139 to R-MegaCHOEP. 130 patients in the R-CHOEP-14 group and 132 in the R-MegaCHOEP group were included in the intention-to-treat population. After a median of 42 months (IQR 29-59), 3-year event-free survival was 69.5% (95% CI 61.3-77.7) in the R-CHOEP-14 group and 61.4% (52.8-70.0) in the R-MegaCHOEP group (p=0.14; hazard ratio 1.3, 95% CI 0.9-2.0). All 128 evaluable patients treated with R-MegaCHOEP had grade 4 leucopenia, as did 48 (58.5%) of 82 patients with documented blood counts in the R-CHOEP-14 group. All 128 evaluable patients in the R-MegaCHOEP group had grade 3-4 thrombocytopenia, as did 26 (33.8%) of 77 patients in the R-CHOEP-14 group with documented blood counts. The most important non-haematological grade 3 or 4 adverse event was infection, which occurred in 96 (75.0%) of 128 patients treated with R-MegaCHOEP and in 40 (31.3%) of 128 patients treated with R-CHOEP-14. INTERPRETATION: In young patients with high-risk aggressive B-cell lymphoma, R-MegaCHOEP was not superior to conventional R-CHOEP therapy and was associated with significantly more toxic effects. R-CHOEP-14 with or without radiotherapy remains a treatment option for these patients, with encouraging efficacy. FUNDING: Deutsche Krebshilfe.

Authors: N. Schmitz, M. Nickelsen, M. Ziepert, M. Haenel, P. Borchmann, C. Schmidt, A. Viardot, M. Bentz, N. Peter, G. Ehninger, G. Doelken, C. Ruebe, L. Truemper, A. Rosenwald, M. Pfreundschuh, M. Loeffler, B. Glass

Date Published: 22nd Nov 2012

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

Copy number variants in lipid metabolism genes are associated with gallstones disease in men
Genetical Statistics and Systems Biology

Abstract (Expand)

Gallstones Disease (GSD) is one of the most common digestive diseases requiring hospitalization and surgical procedures in the world. GSD has a high prevalence in populations with European or Amerindian … ancestry (10-20%) and the influence of genetic factors is broadly acknowledged. However, known genetic variants do not entirely explain the disease heritability suggesting that additional genetic variants remain to be identified. Here, we examined the association of copy number variants (CNVs) with GSD in a sample of 4778 individuals (1929 GSD cases and 2849 controls) including two European cohorts from Germany (n = 3702) and one admixed Latin American cohort from Chile (n = 1076). We detected 2936 large and rare CNVs events (size \textgreater 100 kb, frequency \textless 1%). Case-control burden analysis and generalized linear regression models revealed significant association of CNVs with GSD in men, with the strongest effect observed with CNVs overlapping lipid metabolism genes (p-value = 6.54 \times 10-4; OR = 2.76; CI 95% = 1.53-4.89). Our results indicate a clear link between CNVs and GSD in men and provides additional evidence that the genetic components of risk for GSD are complex, can be sex specific and include CNVs affecting genes involved in lipid metabolism.

Authors: Eduardo Pérez-Palma, Bernabé I. Bustos, Dennis Lal, Stephan Buch, Lorena Azocar, Mohammad Reza Toliat, Wolfgang Lieb, Andre Franke, Sebastian Hinz, Greta Burmeister, Witigo von Shönfels, Clemens Schafmayer, Peter Ahnert, Henry Völzke, Uwe Völker, Georg Homuth, Markus M. Lerch, Klaus Puschel, Rodrigo A. Gutiérrez, Jochen Hampe, Peter Nürnberg, Juan Francisco Miquel, Giancarlo V. de Ferrari

Date Published: 1st Feb 2020

Publication Type: Journal article

Correction to: Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract

After publication of the original article [1], we were notified that columns in Table 2 were erroneously displayed.

Authors: Nasim Mavaddat, Antonis C. Antoniou, Thea M. Mooij, Maartje J. Hooning, Bernadette A. Heemskerk-Gerritsen, Catherine Noguès, Marion Gauthier-Villars, Olivier Caron, Paul Gesta, Pascal Pujol, Alain Lortholary, Daniel Barrowdale, Debra Frost, D. Gareth Evans, Louise Izatt, Julian Adlard, Ros Eeles, Carole Brewer, Marc Tischkowitz, Alex Henderson, Jackie Cook, Diana Eccles, Klaartje van Engelen, Marian J. E. Mourits, Margreet G. E. M. Ausems, Linetta B. Koppert, John L. Hopper, Esther M. John, Wendy K. Chung, Irene L. Andrulis, Mary B. Daly, Saundra S. Buys, Javier Benitez, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Christian F. Singer, Yen Tan, Edith Olah, Marie Navratilova, Lenka Foretova, Anne-Marie Gerdes, Marie-José Roos-Blom, Flora E. van Leeuwen, Brita Arver, Håkan Olsson, Rita K. Schmutzler, Christoph Engel, Karin Kast, Kelly-Anne Phillips, Mary Beth Terry, Roger L. Milne, David E. Goldgar, Matti A. Rookus, Nadine Andrieu, Douglas F. Easton

Date Published: 1st Dec 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Correlation of the E/E'-ratio to NT-BNP: echocardiographic subanalysis of the LIFE-Adult-Study
LIFE Adult

Abstract (Expand)

The E/E'-ratio is used as a surrogate parameter for the estimation of the left ventricular enddiastolic pressure. It is assumed that chronic systolic and diastolic heart failure is associated with … E/E'-values of more than 15 or at least with intermediate values between 9 – 5. The aim of the present retrospective analysis of the epidemiological echocardiographic cohort of the LIFE-Adult study (Leipzig Research Centre for Civilization Diseases) was to evaluate the correlation of NT-BNP (N-terminales propeptid BNP) values to the E/E'-ratio by the assessment of left ventricular diastolic function in this cohort. In 773 participants (pts) standardised transthoracic echocardiography was performed and in 748 pts NT-BNP was analysed. The E/E'-ratio was determined according to the international recommendations by measuring the maximum velocity of the early diastolic inflow by pulsed wave Doppler echocardiography and the basal septal maximum myocardial velocity by tissue Doppler echocardiography at early diastole. NT-BNP was determined using commercially available diagnostic tests. Pathological NT-BNP levels were assumed in the range > 222pg/ml. Normal E/E'-ratios as well as normal NT-BNP levels were observed in 91% of all participants. In 1.4% of the pts elevated NT-BNP levels were found in the presence of normal E/E'-ratio. In contrast in 1.1% of the pts elevated E/E'-ratios were found in the presence of normal NT-BNP levels. Most of the pts with heart failure detected by NT-BNP vales > 222pg/ml also showed intermediate E/E'-ratios between 9 and 15 (42pts). In only 0.8% of the pts (5 pts) significantly elevated E/E'-ratios > 15 and pathological NT-BNP levels could be observed (see fig). Only 4 pts with elevated NT-BNP values showed left ventricular systolic dysfunction. E/E'-ratio has to be verified to be suitable for the detection of heart failure patients. The present data show that E/E'-ratio of > 15 is not well correlated to increased NT-BNP levels.

Authors: S. Stöbe, A. Hagendorff, S. Zeynalova, S. Tautenhahn, S. Wirkner, F. Gerardo, D. Jurisch, D. Pfeiffer, M. Loeffler

Date Published: 18th Aug 2016

Publication Type: Journal article

Cortical differences in preliterate children at familiar risk of dyslexia are similar to those observed in dyslexic readers
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Indra Kraft, Riccardo Cafiero, Gesa Schaadt, Jens Brauer, Nicole E. Neef, Bent Müller, Holger Kirsten, Arndt Wilcke, Johannes Boltze, Angela D. Friederici, Michael A. Skeide

Date Published: 24th Aug 2015

Publication Type: Journal article

Cost-effectiveness of different strategies to prevent breast and ovarian cancer in German women with a BRCA 1 or 2 mutation
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND Women with a BRCA1 or BRCA2 mutation are at increased risk of developing breast and/or ovarian cancer. This economic modeling study evaluated different preventive interventions for 30-year-old …d women with a confirmed BRCA (1 or 2) mutation. METHODS A Markov model was developed to estimate the costs and benefits [i.e., quality-adjusted life years (QALYs), and life years gained (LYG)] associated with prophylactic bilateral mastectomy (BM), prophylactic bilateral salpingo-oophorectomy (BSO), BM plus BSO, BM plus BSO at age 40, and intensified surveillance. Relevant input data was obtained from a large German database including 5902 women with BRCA 1 or 2, and from the literature. The analysis was performed from the German Statutory Health Insurance (SHI) perspective. In order to assess the robustness of the results, deterministic and probabilistic sensitivity analyses were performed. RESULTS With costs of \text€29,434 and a gain in QALYs of 17.7 (LYG 19.9), BM plus BSO at age 30 was less expensive and more effective than the other strategies, followed by BM plus BSO at age 40. Women who were offered the surveillance strategy had the highest costs at the lowest gain in QALYs/LYS. In the probabilistic sensitivity analysis, the probability of cost-saving was 57% for BM plus BSO. At a WTP of 10,000 \text€ per QALY, the probability of the intervention being cost-effective was 80%. CONCLUSIONS From the SHI perspective, undergoing BM plus immediate BSO should be recommended to BRCA 1 or 2 mutation carriers due to its favorable comparative cost-effectiveness.

Authors: Dirk Müller, Marion Danner, Kerstin Rhiem, Björn Stollenwerk, Christoph Engel, Linda Rasche, Lisa Borsi, Rita Schmutzler, Stephanie Stock

Date Published: 1st Apr 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Cost-utility analysis of a preventive home visit program for older adults in Germany.
LIFE Adult

Abstract (Expand)

BACKGROUND: Most older adults want to live independently in a familiar environment instead of moving to a nursing home. Preventive home visits based on multidimensional geriatric assessment can be one … strategy to support this preference and might additionally reduce health care costs, due to the avoidance of costly nursing home admissions. The purpose of this study was to analyse the cost-effectiveness of preventive home visits from a societal perspective in Germany. METHODS: This study is part of a multi-centre, non-blinded, randomised controlled trial aiming at the reduction of nursing home admissions. Participants were older than 80 years and living at home. Up to three home visits were conducted to identify self-care deficits and risk factors, to present recommendations and to implement solutions. The control group received usual care. A cost-utility analysis using quality-adjusted life years (QALY) based on the EQ-5D was performed. Resource utilization was assessed by means of the interview version of a patient questionnaire. A cost-effectiveness acceptability curve controlled for prognostic variables was constructed and a sensitivity analysis to control for the influence of the mode of QALY calculation was performed. RESULTS: 278 individuals (intervention group: 133; control group: 145) were included in the analysis. During 18 months follow-up mean adjusted total cost (mean: +4,401 EUR; bootstrapped standard error: 3,019.61 EUR) and number of QALY (mean: 0.0061 QALY; bootstrapped standard error: 0.0388 QALY) were higher in the intervention group, but differences were not significant. For preventive home visits the probability of an incremental cost-effectiveness ratio <50,000 EUR per QALY was only 15%. The results were robust with respect to the mode of QALY calculation. CONCLUSIONS: The evaluated preventive home visits programme is unlikely to be cost-effective. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT00644826.

Authors: C. Brettschneider, T. Luck, S. Fleischer, G. Roling, K. Beutner, M. Luppa, J. Behrens, S. G. Riedel-Heller, H. H. Konig

Date Published: 3rd Apr 2015

Publication Type: Not specified

Could High Mental Demands at Work Offset the Adverse Association Between Social Isolation and Cognitive Functioning? Results of the Population-Based LIFE-Adult-Study.
LIFE Adult

Abstract (Expand)

OBJECTIVES: The study investigated whether high mental demands at work, which have shown to promote a good cognitive functioning in old age, could offset the adverse association between social isolation … and cognitive functioning. METHODS: Based on data from the population-based LIFE-Adult-Study, the association between cognitive functioning (Verbal Fluency Test, Trail Making Test B) and social isolation (Lubben Social Network Scale) as well as mental demands at work (O*NET database) was analyzed via linear regression analyses adjusted for age, sex, education, and sampling weights. RESULTS: Cognitive functioning was significantly lower in socially isolated individuals and in individuals working in low mental demands jobs-even in old age after retirement and even after taking into account the educational level. An interaction effect suggested stronger effects of mental demands at work in socially isolated than nonisolated individuals. CONCLUSIONS: The findings suggest that working in high mental-demand jobs could offset the adverse association between social isolation and cognitive functioning. Further research should evaluate how interventions that target social isolation and enhance mentally demanding activities promote a good cognitive functioning in old age.

Authors: F. S. Rodriguez, M. L. Schroeter, A. V. Witte, C. Engel, M. Loffler, J. Thiery, A. Villringer, T. Luck, S. G. Riedel-Heller

Date Published: 4th Jul 2017

Publication Type: Journal article

Covid-19 Transmission Trajectories-Monitoring the Pandemic in the Worldwide Context.
Task Force COVID-19 Leipzig

Abstract (Expand)

The Covid-19 pandemic is developing worldwide with common dynamics but also with marked differences between regions and countries. These are not completely understood, but presumably, provide a clue … to find ways to mitigate epidemics until strategies leading to its eradication become available. We describe an iteractive monitoring tool available in the internet. It enables inspection of the dynamic state of the epidemic in 187 countries using trajectories that visualize the transmission and removal rates of the epidemic and in this way bridge epi-curve tracking with modelling approaches. Examples were provided which characterize state of epidemic in different regions of the world in terms of fast and slow growing and decaying regimes and estimate associated rate factors. The basic spread of the disease is associated with transmission between two individuals every two-three days on the average. Non-pharmaceutical interventions decrease this value to up to ten days, whereas 'complete lock down' measures are required to stop the epidemic. Comparison of trajectories revealed marked differences between the countries regarding efficiency of measures taken against the epidemic. Trajectories also reveal marked country-specific recovery and death rate dynamics. The results presented refer to the pandemic state in May to July 2020 and can serve as 'working instruction' for timely monitoring using the interactive monitoring tool as a sort of 'seismometer' for the evaluation of the state of epidemic, e.g., the possible effect of measures taken in both, lock-down and lock-up directions. Comparison of trajectories between countries and regions will support developing hypotheses and models to better understand regional differences of dynamics of Covid-19.

Authors: H. Loeffler-Wirth, M. Schmidt, H. Binder

Date Published: 20th Jul 2020

Publication Type: Journal article

Human Diseases: COVID-19

Curation-DB: Curating Scientific Data in LIFE
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Introduction LIFE is a epidemiological study aiming at discovering causes of common disorders as well as therapy and diagnostic possibilities. It applies a huge set (currently more then 400) of complex … instruments including different kinds of interviews, questionnaires, and technically founded investigations on thousands of Leipzig inhabitants. Correlations in data, e.g., between diseases on the one hand and a combination of life conditions on the other requires high quality data. Data errors affect this data quality. However, avoiding every error is nearly impossible. Therefore, the captured data routinely needs to be validated and revised (curated) in case of error. Methods From the data-perspective, we differentiate between two main types of data errors, syntax or format errors and semantic errors. Syntax errors mostly occur when the data needs to be converted to change its data type, e.g., from text to number or from text to date/time fields. This is often the case when data is captured as text by the data input system but should be centrally managed and analyzed in a different format. Hence, the data conversion is only successful when the input data contains the data in the right format. Data conversion is applied when the data is transfered from data input systems to the central research database collecting all captured data in an integrated and harmonized form. Corrupted data that cannot be converted to the target data type is replaced by a missing value (also called null value, nil etc.). The definition of a default value is not sufficient since the default usually depends on the corresponding question or measurement input field and can strain analysis results when they are not concerned. Moreover, the definition process for every question/input field would be to time-consuming. Semantic errors are much harder to detect than syntax errors. Typically, they are semantically implausible outliers or are part of other artefacts, e.g.,when data of two input fields is mixed up. Currently, we let the detection of semantic errors to a epidemiological quality analysis that is performed by several statisticians. Conversely, syntax errors can be easily technically detected; they are logged when they occur in the process of transferring data from data input systems to the central research database. With respect to both types of errors, syntax and semantic errors, we designed and implemented a software application called Curation-DB allowing to curate (adapt and change) data. In particular, the system lists the logged syntax errors occurring during the data conversion step daily at night. A user can adapt the current input value by specifying a new (target) value for a listed syntax problem. With this specification, the corresponding input value is replaced by the specified value before the next conversion step is started. This specification process can be iteratively applied for a corresponding input value when the syntax problem is not solved by the current specification. The semantic errors need to be first detected separately. Then, a user can specify value changes replacing an existing value with the new specified one. Results & Discussion The Curation-DB application is already in use. Currently, selected quality managers routinely check the listed syntax errors. There are currently more than 2000 of such errors curated. In near future, we will extend this software to manage rules validating research data semantically to automatically detect obvious semantic errors.

Authors: J. Wagner, A. Kiel, Toralf Kirsten

Date Published: 30th Sep 2013

Publication Type: Not specified

Current practice in nutritional support and its association with mortality in septic patients–results from a national, prospective, multicenter study
SepNet - German Competence Network Sepsis

Abstract (Expand)

OBJECTIVE To identify current clinical practice regarding nutrition and its association with morbidity and mortality in patients with severe sepsis or septic shock in Germany. DESIGN Nationwide …ide prospective, observational, cross-sectional, 1-day point-prevalence study. SETTING The study included 454 intensive care units from a representative sample of 310 hospitals stratified by size. PATIENTS Participants were 415 patients with severe sepsis or septic shock (according to criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Data were collected by on-site audits of trained external study physicians during randomly scheduled visits during 1 yr. Valid data on nutrition were available for 399 of 415 patients. The data showed that 20.1% of patients received exclusively enteral nutrition, 35.1% exclusively parenteral nutrition, and 34.6% mixed nutrition (parenteral and enteral); 10.3% were not fed at all. Patients with gastrointestinal/intra-abdominal infection, pancreatitis or neoplasm of the gastrointestinal tract, mechanical ventilation, or septic shock were less likely to receive exclusively enteral nutrition. Median Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores were significantly different among the nutrition groups. Overall hospital mortality was 55.2%. Hospital mortality was significantly higher in patients receiving exclusively parenteral (62.3%) or mixed nutrition (57.1%) than in patients with exclusively enteral nutrition (38.9%) (p = .005). After adjustment for patient morbidity (Acute Physiology and Chronic Health Evaluation II score, presence of septic shock) and treatment factors (mechanical ventilation), multivariate analysis revealed that the presence of parenteral nutrition was significantly predictive of mortality (odds ratio, 2.09; 95% confidence interval, 1.29-3.37). CONCLUSIONS Patients with severe sepsis or septic shock in German intensive care units received preferentially parenteral or mixed nutrition. The use of parenteral nutrition was associated with an increased risk of death.

Authors: Gunnar Elke, Dirk Schädler, Christoph Engel, Holger Bogatsch, Inez Frerichs, Maximilian Ragaller, Jens Scholz, Frank M. Brunkhorst, Markus Löffler, Konrad Reinhart, Norbert Weiler

Date Published: 2008

Publication Type: Journal article

Human Diseases: disease by infectious agent

Customer-enabled orchestration of complex services: A new paradigm even for health care?
Management of health information systems

Abstract

Not specified

Authors: Alfred Winter, R. Alt, Jan Ehmke, Reinhold Haux, Dirk Mattfeld, A. Oberweis, Barbara Paech

Date Published: 2014

Publication Type: Journal article

Cyclin dependent kinase inhibitor 1 C is a female-specific marker of left ventricular function after acute myocardial infarction
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND A significant proportion of patients develop left ventricular (LV) remodeling leading to heart failure after acute myocardial infarction (AMI). Being able to identify these patients would …d represent a step forward towards personalized medicine. The present study aimed to determine the ability of cyclin dependent kinase inhibitor 1C (CDKN1C) to risk stratify AMI patients, in a sex-specific manner. METHODS CDKN1C expression was measured in blood samples obtained at admission in a test cohort of 447 AMI patients and a validation cohort of 294 patients. The study end-point was LV function assessed by the ejection fraction (EF) at follow-up. RESULTS In the test cohort, CDKN1C was lower in patients with a reduced EF (\textless40%) compared to patients with preserved EF (\geq50%). This observation was specific to women. CDKN1C was a significant univariate predictor of LV function in women only. In multivariable analysis including demographic and clinical parameters, CDKN1C predicted LV function in women (odds ratio [95% confidence interval] 0.44 [0.23-0.82]) but not in men (0.90 [0.70-1.16]). Addition of CDKN1C to a multivariable clinical model reduced the Akaike information criterion, attesting for an incremental predictive value, in women (p = 0.006) but not in men (p = 0.41). Bootstrap internal validation confirmed the added value of CDKN1C in women. The female-specific predictive value of CDKN1C was validated in the independent cohort. CONCLUSION CDKN1C is a novel female-specific biomarker of LV function after AMI.

Authors: Torkia Lalem, Lu Zhang, Markus Scholz, Ralph Burkhardt, Victoria Saccheti, Andrej Teren, Joachim Thiery, Yvan Devaux

Date Published: 2019

Publication Type: Journal article

Cytogenetic and molecular biological characterization of an adult medulloblastoma
Genetical Statistics and Systems Biology

Abstract (Expand)

Medulloblastoma is a malignant invasive embryonal tumor, occurring in children mainly. It is rare in adults (\textless1% of adult brain tumors), and so comprehensive cytogenetic and molecular biological … data on adult medulloblastomas are very limited. Conventional therapies provide disappointing long-term disease control, and new therapeutic options are being tested. We performed comprehensive cytogenetic analyses of an adult medulloblastoma, WHO grade IV, using trypsin-Giemsa staining (GTG-banding), multicolor fluorescence in situ hybridization (M-FISH), and locus-specific FISH, complemented by molecular karyotyping using high-density single nucleotide polymorphism (SNP) arrays. GTG-banding of 25 metaphases revealed 31 structural chromosomal aberrations, predominantly located on chromosomes 4q, 9q, 10q, 11p, and 20q, which were confirmed by M-FISH. Two novel, so far not described translocations were found: t(4;11)(q25;p15) and t(9;20)(p23;p12). GTG-banding, locus-specific FISH, and M-FISH detected numerical changes of chromosomes 8, 14, 18, 19, 20, 21, and 22. Molecular karyotyping by SNP array confirmed chromosomal changes -2p, -10q, -16q, and -Xq and revealed de novo partial uniparental disomy 1q and 9q. Applying an upcoming therapeutic approach, we found that primary medulloblastoma cells were resistant to TRAIL, a novel anticancer cytokine, but could be efficiently sensitized by cotreatment with the proteasome inhibitor bortezomib. Bortezomib-TRAIL cotreatment may serve as a powerful therapeutic option for medulloblastoma patients.

Authors: Heidrun Holland, Ronald Koschny, Wolfgang Krupp, Jürgen Meixensberger, Manfred Bauer, Ralf Schober, Holger Kirsten, Tom M. Ganten, Peter Ahnert

Date Published: 1st Oct 2007

Publication Type: Journal article

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