Filter and export

Publications

958 Publications visible to you, out of a total of 958
Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.
GLA - German Lymphoma Alliance

Abstract (Expand)

Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined … activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.

Authors: B. Chapuy, C. Stewart, A. J. Dunford, J. Kim, A. Kamburov, R. A. Redd, M. S. Lawrence, M. G. M. Roemer, A. J. Li, M. Ziepert, A. M. Staiger, J. A. Wala, M. D. Ducar, I. Leshchiner, E. Rheinbay, A. Taylor-Weiner, C. A. Coughlin, J. M. Hess, C. S. Pedamallu, D. Livitz, D. Rosebrock, M. Rosenberg, A. A. Tracy, H. Horn, P. van Hummelen, A. L. Feldman, B. K. Link, A. J. Novak, J. R. Cerhan, T. M. Habermann, R. Siebert, A. Rosenwald, A. R. Thorner, M. L. Meyerson, T. R. Golub, R. Beroukhim, G. G. Wulf, G. Ott, S. J. Rodig, S. Monti, D. S. Neuberg, M. Loeffler, M. Pfreundschuh, L. Trumper, G. Getz, M. A. Shipp

Date Published: 2nd May 2018

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium … of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

Authors: Timothy R. Rebbeck, Tara M. Friebel, Eitan Friedman, Ute Hamann, Dezheng Huo, Ava Kwong, Edith Olah, Olufunmilayo I. Olopade, Angela R. Solano, Soo-Hwang Teo, Mads Thomassen, Jeffrey N. Weitzel, T. L. Chan, Fergus J. Couch, David E. Goldgar, Torben A. Kruse, Edenir Inêz Palmero, Sue Kyung Park, Diana Torres, Elizabeth J. van Rensburg, Lesley McGuffog, Michael T. Parsons, Goska Leslie, Cora M. Aalfs, Julio Abugattas, Julian Adlard, Simona Agata, Kristiina Aittomäki, Lesley Andrews, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Ella Asseryanis, Leo Auerbach, Jacopo Azzollini, Judith Balmaña, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Andreas Berger, Raanan Berger, Amie M. Blanco, Kathleen R. Blazer, Marinus J. Blok, Valérie Bonadona, Bernardo Bonanni, Angela R. Bradbury, Carole Brewer, Bruno Buecher, Saundra S. Buys, Trinidad Caldes, Almuth Caliebe, Maria A. Caligo, Ian Campbell, Sandrine M. Caputo, Jocelyne Chiquette, Wendy K. Chung, Kathleen B. M. Claes, J. Margriet Collée, Jackie Cook, Rosemarie Davidson, Miguel de La Hoya, Kim de Leeneer, Antoine de Pauw, Capucine Delnatte, Orland Diez, Yuan Chun Ding, Nina Ditsch, Susan M. Domchek, Cecilia M. Dorfling, Carolina Velazquez, Bernd Dworniczak, Jacqueline Eason, Douglas F. Easton, Ros Eeles, Hans Ehrencrona, Bent Ejlertsen, Christoph Engel, Stefanie Engert, D. Gareth Evans, Laurence Faivre, Lidia Feliubadaló, Sandra Fert Ferrer, Lenka Foretova, Jeffrey Fowler, Debra Frost, Henrique C. R. Galvão, Patricia A. Ganz, Judy Garber, Marion Gauthier-Villars, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Giuseppe Giannini, Sophie Giraud, Gord Glendon, Andrew K. Godwin, Mark H. Greene, Jacek Gronwald, Angelica Gutierrez-Barrera, Eric Hahnen, Jan Hauke, Alex Henderson, Julia Hentschel, Frans B. L. Hogervorst, Ellen Honisch, Evgeny N. Imyanitov, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Esther M. John, Joseph Vijai, Katarzyna Kaczmarek, Beth Y. Karlan, Karin Kast, Kconfab Investigators, Sung-Won Kim, Irene Konstantopoulou, Jacob Korach, Yael Laitman, Adriana Lasa, Christine Lasset, Conxi Lázaro, Annette Lee, Min Hyuk Lee, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Noralane M. Lindor, Michel Longy, Jennifer T. Loud, Karen H. Lu, Jan Lubinski, Eva Machackova, Siranoush Manoukian, Véronique Mari, Cristina Martínez-Bouzas, Zoltan Matrai, Noura Mebirouk, Hanne E. J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Ugnius Mickys, Austin Miller, Marco Montagna, Kirsten B. Moysich, Anna Marie Mulligan, Jacob Musinsky, Susan L. Neuhausen, Heli Nevanlinna, Joanne Ngeow, Huu Phuc Nguyen, Dieter Niederacher, Henriette Roed Nielsen, Finn Cilius Nielsen, Robert L. Nussbaum, Kenneth Offit, Anna Öfverholm, Kai-Ren Ong, Ana Osorio, Laura Papi, Janos Papp, Barbara Pasini, Inge Sokilde Pedersen, Ana Peixoto, Nina Peruga, Paolo Peterlongo, Esther Pohl, Nisha Pradhan, Karolina Prajzendanc, Fabienne Prieur, Pascal Pujol, Paolo Radice, Susan J. Ramus, Johanna Rantala, Muhammad Usman Rashid, Kerstin Rhiem, Mark Robson, Gustavo C. Rodriguez, Mark T. Rogers, Vilius Rudaitis, Ane Y. Schmidt, Rita Katharina Schmutzler, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. Side, Jacques Simard, Christian F. Singer, Anne-Bine Skytte, Thomas P. Slavin, Katie Snape, Hagay Sobol, Melissa Southey, Linda Steele, Doris Steinemann, Grzegorz Sukiennicki, Christian Sutter, Csilla I. Szabo, Yen Y. Tan, Manuel R. Teixeira, Mary Beth Terry, Alex Teulé, Abigail Thomas, Darcy L. Thull, Marc Tischkowitz, Silvia Tognazzo, Amanda Ewart Toland, Sabine Topka, Alison H. Trainer, Nadine Tung, Christi J. van Asperen, Annemieke H. van der Hout, Lizet E. van der Kolk, Rob B. van der Luijt, Mattias van Heetvelde, Liliana Varesco, Raymonda Varon-Mateeva, Ana Vega, Cynthia Villarreal-Garza, Anna von Wachenfeldt, Lisa Walker, Shan Wang-Gohrke, Barbara Wappenschmidt, Bernhard H. F. Weber, Drakoulis Yannoukakos, Sook-Yee Yoon, Cristina Zanzottera, Jamal Zidan, Kristin K. Zorn, Christina G. Hutten Selkirk, Peter J. Hulick, Georgia Chenevix-Trench, Amanda B. Spurdle, Antonis C. Antoniou, Katherine L. Nathanson

Date Published: 1st May 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Genetic Regulation of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Plasma Levels and Its Impact on Atherosclerotic Vascular Disease Phenotypes
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is a novel strategy to treat hypercholesterolemia and reduce cardiovascular events. However, the potential role of circulating …g plasma PCSK9 concentrations as a diagnostic and predictive biomarker remains uncertain as of now. Here, we aimed to identify genetic variants associated with plasma PCSK9 and investigate possible causal effects on atherosclerotic vascular disease phenotypes. METHODS We performed the first genome-wide association study of plasma PCSK9 levels in a cohort of suspected and confirmed coronary artery disease (LIFE-Heart; n=3290). RESULTS Several independent variants at the PCSK9 gene locus were associated with circulating PCSK9 levels at genome-wide significance (lead SNP rs11591147, PCSK9-R46L; P=1.94\times10-17). We discovered 4 independent PCSK9 SNPs explaining 4.4% of the variance of plasma PCSK9. In addition, we identified a genome-wide significant locus at chromosome 7p22.1 (rs6957201; P=7.01\times10-9) and 7 suggestive hits (P\textless1\times10-6). Using MR (Mendelian Randomization), we detected significant causal effects of circulating PCSK9 on coronary artery disease status and severity, carotid plaques, and intima-media thickness. CONCLUSIONS Variants at the PCSK9 gene locus seem to be the major genetic determinants of plasma PCSK9 levels with 4 independent variants at the PCSK9 gene locus expressing allelic heterogeneity. The detected MR estimates support the hypothesis of a causal effect of PCSK9 on coronary artery disease and other vascular phenotypes. Other observed genetic associations for PCSK9 require validation in independent cohorts. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00497887.

Authors: Janne Pott, Valentin Schlegel, Andrej Teren, Katrin Horn, Holger Kirsten, Christina Bluecher, Juergen Kratzsch, Markus Loeffler, Joachim Thiery, Ralph Burkhardt, Markus Scholz

Date Published: 1st May 2018

Publication Type: Journal article

3000PA-Towards a National Reference Corpus of German Clinical Language
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

We introduce 3000PA, a clinical document corpus composed of 3,000 EPRs from three different clinical sites, which will serve as the backbone of a national reference language resource for German clinical … NLP. We outline its design principles, results from a medication annotation campaign and the evaluation of a first medication information extraction prototype using a subset of 3000PA.

Authors: U. Hahn, F. Matthies, C. Lohr, Markus Löffler

Date Published: 24th Apr 2018

Publication Type: InProceedings

Pseudotime Dynamics in Melanoma Single-Cell Transcriptomes Reveals Different Mechanisms of Tumor Progression.
Leipzig Melanoma Studies

Abstract (Expand)

Single-cell transcriptomics has been used for analysis of heterogeneous populations of cells during developmental processes and for analysis of tumor cell heterogeneity. More recently, analysis of … pseudotime (PT) dynamics of heterogeneous cell populations has been established as a powerful concept to study developmental processes. Here we perform PT analysis of 3 melanoma short-term cultures with different genetic backgrounds to study specific and concordant properties of PT dynamics of selected cellular programs with impact on melanoma progression. Overall, in our setting of melanoma cells PT dynamics towards higher tumor malignancy appears to be largely driven by cell cycle genes. Single cells of all three short-term cultures show a bipolar expression of microphthalmia-associated transcription factor (MITF) and AXL receptor tyrosine kinase (AXL) signatures. Furthermore, opposing gene expression changes are observed for genes regulated by epigenetic mechanisms suggesting epigenetic reprogramming during melanoma progression. The three melanoma short-term cultures show common themes of PT dynamics such as a stromal signature at initiation, bipolar expression of the MITF/AXL signature and opposing regulation of poised and activated promoters. Differences are observed at the late stage of PT dynamics with high, low or intermediate MITF and anticorrelated AXL signatures. These findings may help to identify targets for interference at different stages of tumor progression.

Authors: H. Loeffler-Wirth, H. Binder, E. Willscher, T. Gerber, M. Kunz

Date Published: 3rd Apr 2018

Publication Type: Not specified

Human Diseases: melanoma

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

Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. … In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67-4.94), CDH1 (OR: 17.04, 95%CI: 3.54-82), CHEK2 (OR: 2.93, 95%CI: 2.29-3.75), PALB2 (OR: 9.53, 95%CI: 6.25-14.51), and TP53 (OR: 7.30, 95%CI: 1.22-43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73-2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors.

Authors: Jan Hauke, Judit Horvath, Eva Groß, Andrea Gehrig, Ellen Honisch, Karl Hackmann, Gunnar Schmidt, Norbert Arnold, Ulrike Faust, Christian Sutter, Julia Hentschel, Shan Wang-Gohrke, Mateja Smogavec, Bernhard H. F. Weber, Nana Weber-Lassalle, Konstantin Weber-Lassalle, Julika Borde, Corinna Ernst, Janine Altmüller, Alexander E. Volk, Holger Thiele, Verena Hübbel, Peter Nürnberg, Katharina Keupp, Beatrix Versmold, Esther Pohl, Christian Kubisch, Sabine Grill, Victoria Paul, Natalie Herold, Nadine Lichey, Kerstin Rhiem, Nina Ditsch, Christian Ruckert, Barbara Wappenschmidt, Bernd Auber, Andreas Rump, Dieter Niederacher, Thomas Haaf, Juliane Ramser, Bernd Dworniczak, Christoph Engel, Alfons Meindl, Rita K. Schmutzler, Eric Hahnen

Date Published: 1st Apr 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Navigate

Health Atlas - Local Data Hub/Leipzig

The Health Atlas - Local Data Hub/Leipzig is an alliance of medical ontologists, medical systems biologists and clinical trials groups to design and implement a multi-functional and quality-assured atlas. It provides models, data and metadata on specific use cases from medical research fields.

Registered Repository

re3data.org Badge
Powered by
 (v.1.13.0-master)
Health Atlas | Funding and Programmes | Credits | Terms & Conditions | Privacy Policy | Imprint
Copyright © 2008 - 2021 The University of Manchester and HITS gGmbH
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig

By continuing to use this site you agree to the use of cookies