Publications

9 Publications visible to you, out of a total of 9

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 carrierss 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

Abstract (Expand)

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p\textless0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 \times 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 \times 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

Authors: Ana Osorio, Roger L. Milne, Karoline Kuchenbaecker, Tereza Vaclová, Guillermo Pita, Rosario Alonso, Paolo Peterlongo, Ignacio Blanco, Miguel de La Hoya, Mercedes Duran, Orland Díez, Teresa Ramón y Cajal, Irene Konstantopoulou, Cristina Martínez-Bouzas, Raquel Andrés Conejero, Penny Soucy, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Swe-Brca, Brita Arver, Johanna Rantala, Niklas Loman, Hans Ehrencrona, Olufunmilayo I. Olopade, Mary S. Beattie, Susan M. Domchek, Katherine Nathanson, Timothy R. Rebbeck, Banu K. Arun, Beth Y. Karlan, Christine Walsh, Jenny Lester, Esther M. John, Alice S. Whittemore, Mary B. Daly, Melissa Southey, John Hopper, Mary B. Terry, Saundra S. Buys, Ramunas Janavicius, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Linda Steele, Susan L. Neuhausen, Yuan Chun Ding, Thomas v. O. Hansen, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Mar Infante, Belén Herráez, Leticia Thais Moreno, Jeffrey N. Weitzel, Josef Herzog, Kisa Weeman, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Bernardo Bonanni, Frederique Mariette, Sara Volorio, Alessandra Viel, Liliana Varesco, Laura Papi, Laura Ottini, Maria Grazia Tibiletti, Paolo Radice, Drakoulis Yannoukakos, Judy Garber, Steve Ellis, Debra Frost, Radka Platte, Elena Fineberg, Gareth Evans, Fiona Lalloo, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Diana Eccles, Jackie Cook, Shirley Hodgson, Carole Brewer, Marc Tischkowitz, Fiona Douglas, Mary Porteous, Lucy Side, Lisa Walker, Patrick Morrison, Alan Donaldson, John Kennedy, Claire Foo, Andrew K. Godwin, Rita Katharina Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hans Jörg Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Andrea Gehrig, Dominique Stoppa-Lyonnet, Olga M. Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Bruce Poppe, Kathleen Claes, Marion Piedmonte, Kathy Tucker, Floor Backes, Gustavo Rodríguez, Wendy Brewster, Katie Wakeley, Thomas Rutherford, Trinidad Caldés, Heli Nevanlinna, Kristiina Aittomäki, Matti A. Rookus, Theo A. M. van Os, Lizet van der Kolk, J. L. de Lange, Hanne E. J. Meijers-Heijboer, A. H. van der Hout, Christi J. van Asperen, Encarna B. Gómez Garcia, Nicoline Hoogerbrugge, J. Margriet Collée, Carolien H. M. van Deurzen, Rob B. van der Luijt, Peter Devilee, Hebon, Edith Olah, Conxi Lázaro, Alex Teulé, Mireia Menéndez, Anna Jakubowska, Cezary Cybulski, Jacek Gronwald, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Oskar Th Johannsson, Christine Maugard, Marco Montagna, Silvia Tognazzo, Manuel R. Teixeira, Sue Healey, Kconfab Investigators, Curtis Olswold, Lucia Guidugli, Noralane Lindor, Susan Slager, Csilla I. Szabo, Joseph Vijai, Mark Robson, Noah Kauff, Liying Zhang, Rohini Rau-Murthy, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Andreas Berger, Catherine M. Phelan, Mark H. Greene, Phuong L. Mai, Flavio Lejbkowicz, Irene Andrulis, Anna Marie Mulligan, Gord Glendon, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Mads Thomassen, Torben A. Kruse, Uffe Birk Jensen, Eitan Friedman, Yael Laitman, Shani Paluch Shimon, Jacques Simard, Douglas F. Easton, Kenneth Offit, Fergus J. Couch, Georgia Chenevix-Trench, Antonis C. Antoniou, Javier Benitez

Date Published: 3rd Apr 2014

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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