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1. Diagnostic chest X-rays and breast cancer risk among women with a hereditary predisposition to breast cancer unexplained by a BRCA1 or BRCA2 mutation

Author

Maximiliano Ribeiro Guerra, Juliette Coignard, Séverine Eon-Marchais, Marie-Gabrielle Dondon, Dorothée Le Gal, Juana Beauvallet, Noura Mebirouk, Muriel Belotti, Olivier Caron, Marion Gauthier-Villars, Isabelle Coupier, Bruno Buecher, Alain Lortholary, Jean-Pierre Fricker, Paul Gesta, Catherine Noguès, Laurence Faivre, Pascaline Berthet, Elisabeth Luporsi, Capucine Delnatte, Valérie Bonadona, Christine M. Maugard, Pascal Pujol, Christine Lasset, Michel Longy, Yves-Jean Bignon, Claude Adenis-Lavignasse, Laurence Venat-Bouvet, Hélène Dreyfus, Laurence Gladieff, Isabelle Mortemousque, Séverine Audebert-Bellanger, Florent Soubrier, Sophie Giraud, Sophie Lejeune-Dumoulin, Jean-Marc Limacher, Jean Chiesa, Anne Fajac, Anne Floquet, François Eisinger, Julie Tinat, Sandra Fert-Ferrer, Chrystelle Colas, Thierry Frebourg, Francesca Damiola, Laure Barjhoux, Eve Cavaciuti, Sylvie Mazoyer, Anne Tardivon, Fabienne Lesueur, Dominique Stoppa-Lyonnet, and Nadine Andrieu

Subjects
Breast cancer, X-ray exposure, Low dose, High-risk population, DNA repair genes, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation. Methods We evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC. Results Chest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure. Conclusion Ever/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene. Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.

Published
2021
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2. Data from Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Author

Antonis C. Antoniou, Douglas F. Easton, Georgia Chenevix-Trench, Beth Karlan, Christine Walsh, Jenny Gross, Kate Nathanson, Simon A. Gayther, Lara Sucheston, Kunle Odunsi, Mary Beattie, Robert Nussbaum, Susan L. Neuhausen, Linda Steele, Karin Henriksson, Anna von Wachenfeld, Johanna Rantala, Paolo Aretini, Maria Caligo, Torben Kruse, Anne-Marie Gerdes, Mads Thomassen, Kevin Sweet, Leigha Senter, Amanda Ewart Toland, Evgeny Imyanitov, Anna Sokolenko, Mark H. Greene, Phuong L. Mai, Christine Rappaport, Muy-Kheng Tea, Christian F. Singer, Mia M. Gaudet, Rita Sakr, Kenneth Offit, Csilla Szabo, Noralane M. Lindor, Vernon S. Pankratz, Zachary Fredericksen, Xianshu Wang, Judy E. Garber, Nadine Tung, Wendy Rubinstein, Timothy R. Rebbeck, Stephen Fox, Max Yan, Emma D'Andrea, Simona Agata, Marco Montagna, Jacques Simard, Martine Dumont, Rosa B. Barkardottir, Adalgeir Arason, Bjarni A. Agnarsson, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Kristiina Aittomäki, Päivi Heikkilä, Tuomas Heikkinen, Carmen Cañadas, Miguel de la Hoya, Trinidad Caldes, Beth N. Peshkin, Claudine Isaacs, Laure Barjhoux, Muriel Belotti, Dominique Stoppa-Lyonnet, Heidrun Gevensleben, Ines Schönbuchner, Raymonda Varon-Mateeva, Sabine Preisler-Adams, Doroteha Gadzicki, Helmut Deissler, Christian Sutter, Dieter Niederacher, Norbert Arnold, Karin Kast, Alfons Meindl, Barbara Wappenschmidt, Rita K. Schmutzler, Andrew K. Godwin, JoEllen Weaver, Catherine Houghton, Lucy E. Side, Mark T. Rogers, Lisa Walker, Carole Brewer, D. Gareth Evans, Debra Frost, Susan Peock, Rob B. van der Luijt, Mieke Kriege, Frans B. Hogervorst, Muhammad U. Rashid, Ute Hamann, Paolo Radice, Laura Ottini, Anna Laura Putignano, Riccardo Dolcetti, Barbara Pasini, Sara Volorio, Monica Barile, Bernard Peissel, Siranoush Manoukian, Javier Benítez, Alexandra Stavropoulou, Ana Osorio, Finn C. Nielsen, Thomas V. O. Hansen, Laima Tihomirova, Ramunas Janavicius, Esther M. John, Frances O'Malley, David Goldgar, Mary Beth Terry, Melissa C. Southey, Olga M. Sinilnikova, Sue Healey, Lesley McGuffog, Christoph Engel, Fergus J. Couch, Anna Marie Mulligan, Mark Sherman, Mark Robson, Amanda Spurdle, Susan J. Ramus, Heli Nevanlinna, Diana Eccles, Susan M. Domchek, Irene L. Andrulis, Daniel Barrowdale, and Nasim Mavaddat

Abstract

Background: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.Methods: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.Results: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10−5), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10−6). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10−13 for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0–12.6 and PR-positive OR = 1.7, 95% CI: 1.3–2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4–4.4; P = 4.4 × 10−14), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18–0.35; P = 2.3 × 10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%).Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 21(1); 134–47. ©2011 AACR.

Published
2023
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3. Supplementary Table 2 from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

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

Abstract

Supplementary Table 2. Results of the statistical analyses in BRCA mutation carriers.

Published
2023
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4. Supplementary Table 1 from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

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

Abstract

Supplementary Table 1. The 3,248 SNPs included in the study

Published
2023
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5. Supplementary Table 3 from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

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

Abstract

Supplementary Table 3. Results of the statistical analyses of SNPs from project 12 in BRCA-mutation carriers affected or non-affected with breast cancer and according to their estrogen receptor status.

Published
2023
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6. Supplementary Tables 1-9 from Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Author

Antonis C. Antoniou, Douglas F. Easton, Georgia Chenevix-Trench, Beth Karlan, Christine Walsh, Jenny Gross, Kate Nathanson, Simon A. Gayther, Lara Sucheston, Kunle Odunsi, Mary Beattie, Robert Nussbaum, Susan L. Neuhausen, Linda Steele, Karin Henriksson, Anna von Wachenfeld, Johanna Rantala, Paolo Aretini, Maria Caligo, Torben Kruse, Anne-Marie Gerdes, Mads Thomassen, Kevin Sweet, Leigha Senter, Amanda Ewart Toland, Evgeny Imyanitov, Anna Sokolenko, Mark H. Greene, Phuong L. Mai, Christine Rappaport, Muy-Kheng Tea, Christian F. Singer, Mia M. Gaudet, Rita Sakr, Kenneth Offit, Csilla Szabo, Noralane M. Lindor, Vernon S. Pankratz, Zachary Fredericksen, Xianshu Wang, Judy E. Garber, Nadine Tung, Wendy Rubinstein, Timothy R. Rebbeck, Stephen Fox, Max Yan, Emma D'Andrea, Simona Agata, Marco Montagna, Jacques Simard, Martine Dumont, Rosa B. Barkardottir, Adalgeir Arason, Bjarni A. Agnarsson, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Kristiina Aittomäki, Päivi Heikkilä, Tuomas Heikkinen, Carmen Cañadas, Miguel de la Hoya, Trinidad Caldes, Beth N. Peshkin, Claudine Isaacs, Laure Barjhoux, Muriel Belotti, Dominique Stoppa-Lyonnet, Heidrun Gevensleben, Ines Schönbuchner, Raymonda Varon-Mateeva, Sabine Preisler-Adams, Doroteha Gadzicki, Helmut Deissler, Christian Sutter, Dieter Niederacher, Norbert Arnold, Karin Kast, Alfons Meindl, Barbara Wappenschmidt, Rita K. Schmutzler, Andrew K. Godwin, JoEllen Weaver, Catherine Houghton, Lucy E. Side, Mark T. Rogers, Lisa Walker, Carole Brewer, D. Gareth Evans, Debra Frost, Susan Peock, Rob B. van der Luijt, Mieke Kriege, Frans B. Hogervorst, Muhammad U. Rashid, Ute Hamann, Paolo Radice, Laura Ottini, Anna Laura Putignano, Riccardo Dolcetti, Barbara Pasini, Sara Volorio, Monica Barile, Bernard Peissel, Siranoush Manoukian, Javier Benítez, Alexandra Stavropoulou, Ana Osorio, Finn C. Nielsen, Thomas V. O. Hansen, Laima Tihomirova, Ramunas Janavicius, Esther M. John, Frances O'Malley, David Goldgar, Mary Beth Terry, Melissa C. Southey, Olga M. Sinilnikova, Sue Healey, Lesley McGuffog, Christoph Engel, Fergus J. Couch, Anna Marie Mulligan, Mark Sherman, Mark Robson, Amanda Spurdle, Susan J. Ramus, Heli Nevanlinna, Diana Eccles, Susan M. Domchek, Irene L. Andrulis, Daniel Barrowdale, and Nasim Mavaddat

Abstract

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Published
2023
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7. Data from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

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

Abstract

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 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. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.

Published
2023
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8. GEMO, a National Resource to Study Genetic Modifiers of Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Pathogenic Variant Carriers

Author

Fabienne Lesueur, Noura Mebirouk, Yue Jiao, Laure Barjhoux, Muriel Belotti, Maïté Laurent, Mélanie Léone, Claude Houdayer, Brigitte Bressac-de Paillerets, Dominique Vaur, Hagay Sobol, Catherine Noguès, Michel Longy, Isabelle Mortemousque, Sandra Fert-Ferrer, Emmanuelle Mouret-Fourme, Pascal Pujol, Laurence Venat-Bouvet, Yves-Jean Bignon, Dominique Leroux, Isabelle Coupier, Pascaline Berthet, Véronique Mari, Capucine Delnatte, Paul Gesta, Marie-Agnès Collonge-Rame, Sophie Giraud, Valérie Bonadona, Amandine Baurand, Laurence Faivre, Bruno Buecher, Christine Lasset, Marion Gauthier-Villars, Francesca Damiola, Sylvie Mazoyer, Sandrine M. Caputo, Nadine Andrieu, Dominique Stoppa-Lyonnet, and GEMO Study Collaborators

Subjects
breast cancer, BRCA1/2 mutation carriers, pathogenic variant (PV), DNA banking, genetic epidemiology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2018
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9. Cancer Risks Associated With

Author

Shuai, Li, Valentina, Silvestri, Goska, Leslie, Timothy R, Rebbeck, Susan L, Neuhausen, John L, Hopper, Henriette Roed, Nielsen, Andrew, Lee, Xin, Yang, Lesley, McGuffog, Michael T, Parsons, Irene L, Andrulis, Norbert, Arnold, Muriel, Belotti, Åke, Borg, Bruno, Buecher, Saundra S, Buys, Sandrine M, Caputo, Wendy K, Chung, Chrystelle, Colas, Sarah V, Colonna, Jackie, Cook, Mary B, Daly, Miguel, de la Hoya, Antoine, de Pauw, Hélène, Delhomelle, Jacqueline, Eason, Christoph, Engel, D Gareth, Evans, Ulrike, Faust, Tanja N, Fehm, Florentia, Fostira, George, Fountzilas, Megan, Frone, Vanesa, Garcia-Barberan, Pilar, Garre, Marion, Gauthier-Villars, Andrea, Gehrig, Gord, Glendon, David E, Goldgar, Lisa, Golmard, Mark H, Greene, Eric, Hahnen, Ute, Hamann, Helen, Hanson, Tiara, Hassan, Julia, Hentschel, Judit, Horvath, Louise, Izatt, Ramunas, Janavicius, Yue, Jiao, Esther M, John, Beth Y, Karlan, Sung-Won, Kim, Irene, Konstantopoulou, Ava, Kwong, Anthony, Laugé, Jong Won, Lee, Fabienne, Lesueur, Noura, Mebirouk, Alfons, Meindl, Emmanuelle, Mouret-Fourme, Hannah, Musgrave, Joanne, Ngeow Yuen Yie, Dieter, Niederacher, Sue K, Park, Inge Sokilde, Pedersen, Juliane, Ramser, Susan J, Ramus, Johanna, Rantala, Muhammad U, Rashid, Florian, Reichl, Julia, Ritter, Andreas, Rump, Marta, Santamariña, Claire, Saule, Gunnar, Schmidt, Rita K, Schmutzler, Leigha, Senter, Saba, Shariff, Christian F, Singer, Melissa C, Southey, Dominique, Stoppa-Lyonnet, Christian, Sutter, Yen, Tan, Soo Hwang, Teo, Mary Beth, Terry, Mads, Thomassen, Marc, Tischkowitz, Amanda E, Toland, Diana, Torres, Ana, Vega, Sebastian A, Wagner, Shan, Wang-Gohrke, Barbara, Wappenschmidt, Bernhard H F, Weber, Drakoulis, Yannoukakos, Amanda B, Spurdle, Douglas F, Easton, Georgia, Chenevix-Trench, Laura, Ottini, and Antonis C, Antoniou

Subjects
BRCA2 Protein, Male, Ovarian Neoplasms, Risk, Heterozygote, BRCA1 Protein, Infant, Newborn, Breast Neoplasms, Breast Neoplasms, Male, Pancreatic Neoplasms, Mutation, Humans, Female, Genetic Predisposition to Disease
Abstract

To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) inWe used data from 3,184In addition to female breast and ovarian cancers

Published
2022

10. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author

Marco Montagna, Mark E. Robson, Daniel Barrowdale, Mark H. Greene, Adrià López-Fernández, Miquel Angel Pujana, Paul Brennan, Lucy Side, Jackie Cook, Munaza Ahmed, Christi J. van Asperen, Katherine L. Nathanson, Ian G. Campbell, Shan Wang-Gohrke, Gero Kramer, Debra Frost, Noura Mebirouk, Angel Izquierdo, Conxi Lázaro, Douglas F. Easton, Joe Dennis, Kenneth Offit, Esther Darder, Stefania Tommasi, Angela Toss, Brca, Virginia Valentini, Tu Nguyen-Dumont, Charlotte Kvist Lautrup, Manuel R. Teixeira, Mads Thomassen, Xin Yang, Susan M. Domchek, Valentina Silvestri, Paolo Radice, Marta Venturelli, Joseph Vijai, Pedro Pinto, Caroline Pottinger, Karina Rønlund, Lone Kroeldrup, Paul A. James, Alan Donaldson, Rita K. Schmutzler, Muriel Belotti, Kim De Leeneer, Lesley McGuffog, Susan L. Neuhausen, Amanda E. Toland, Siranoush Manoukian, Vishakha Tripathi, Adalgeir Arason, Pascaline Berthet, Linda Steele, Judit Horvath, Gord Glendon, Goska Leslie, Eva Gross, Anna Coppa, D. J. Gallagher, Payal D. Shah, Hebon Investigators, Alfons Meindl, Orland Diez, Irene L. Andrulis, Angela F. Brady, Giuseppe Damante, Paolo Peterlongo, Ana Sánchez de Abajo, Maria A. Caligo, Alison H. Trainer, Sophie Giraud, Saba Sharif, Christian Sutter, Johanna Rantala, Javier Benitez, Mark T. Rogers, kConFab Investigators, Lídia Feliubadaló, Inge Søkilde Pedersen, Annabeth Høgh Petersen, Jesús del Valle, Agostino Bucalo, Andrea Gehrig, Megan N. Frone, Judith Balmaña, Marc Tischkowitz, Thomas Hansen, Joan Brunet, Ines Zanna, Torben A Kruse, Carole Brewer, Bernard Peissel, Helen Gregory, Mary Porteous, Rosa B. Barkardottir, Andreas Rump, Ros Eeles, Anna Whaite, Saundra S. Buys, Fabienne Lesueur, Lisa Walker, Laura Ottini, Louise Izatt, Antonis C. Antoniou, Georgia Chenevix-Trench, Susanne E. Boonen, Hayley Cassingham, Jacques Simard, Christoph Engel, Patrick J. Morrison, Lise Lotte Christensen, Giulia Cini, Alvaro N.A. Monteiro, Kathleen Claes, Jacqueline Eason, Zoltan Matrai, Uffe Birk Jensen, Kristiina Aittomäki, Ramunas Janavicius, Olufunmilayo I. Olopade, Bjarni A. Agnarsson, Kara N. Maxwell, Julian Barwell, Bernd Auber, Julian Adlard, Esther M. John, Alex Teulé, Miguel de la Hoya, Darcy L. Thull, David E. Goldgar, Alessandra Viel, Dominique Stoppa-Lyonnet, Barbara Wappenschmidt, Phuong L. Mai, Taru A. Muranen, Eric Hahnen, Fergus J. Couch, Laura Matricardi, Domenico Palli, Yen Y. Tan, Julia Hentschel, Florentia Fostira, Ute Hamann, Trinidad Caldés, Rosemarie Davidson, Daniel R. Barnes, Åke Borg, Pedro Pérez-Segura, Aniko Bozsik, Yuan Chun Ding, Dieter Niederacher, Heli Nevanlinna, Helen Hanson, Norbert Arnold, Robin de Putter, Juliane Ramser, Alex Murray, Laura Cortesi, Christian F. Singer, Jacopo Azzollini, Zsofia K. Stadler, Oskar T. Johannsson, Andrew K. Godwin, D. Gareth Evans, Edith Olah, Michael T. Parsons, Medicum, Research Programs Unit, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki University Hospital Area, Research Program in Systems Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Clinicum, Institut Català de la Salut, [Barnes DR, Leslie G, McGuffog L, Dennis J, Yang X] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Silvestri V] Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. [Balmaña J] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Oncology, Male, Cancer Research, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Diàtesi, polygenic, male breast cancer, PRS, Medical Oncology, Prostate cancer, Breast cancer, 0302 clinical medicine, Prostate, Risk Factors, Medicine and Health Sciences, 80 and over, genetics, skin and connective tissue diseases, Aged, 80 and over, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], 0303 health sciences, education.field_of_study, BRCA1 Protein, Men, Articles, ASSOCIATION, Single Nucleotide, prostate cancer, OVARIAN, BRCA1, BRCA2, 3. Good health, Mutation carriers, medicine.anatomical_structure, Ovarian, 030220 oncology & carcinogenesis, Male breast cancer, Pròstata - Càncer - Aspectes genètics, BRCA2 Protein, Genetic Predisposition to Disease, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Risk Assessment, Breast Neoplasms, Prostatic Neoplasms, AcademicSubjects/MED00010, medicine.medical_specialty, Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms [DISEASES], Urology, 3122 Cancers, Population, Single-nucleotide polymorphism, MUTATION CARRIERS, Càncer de mama, Association, 03 medical and health sciences, Internal medicine, medicine, Polymorphism, education, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], 030304 developmental biology, Aged, Càncer de pròstata, business.industry, Cancer, Odds ratio, medicine.disease, neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata [ENFERMEDADES], Homes, Mama - Càncer - Aspectes genètics, business
Abstract

Breast and prostate cancer risks; Pathogenic variant Riscos de càncer de mama i pròstata; Variants patogèniques Riesgos de cáncer de mama y próstata; Variantes patogénicas Background Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management. The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861 and PPRPGM-Nov20\100002. The research leading to these results has received funding from the Italian Association for Cancer Research (AIRC) under IG 2018 - ID. 21389 and the Italian League for the Fight Against Cancer (LILT) under IG 2019 projects, P.I. Ottini Laura and Italian Ministry of Education, Universities and Research-Dipartimenti di Eccellenza-L. 232/2016. CIMBA: GCT is a National Health and Medical Research Council (NHMRC) Research Fellow. iCOGS and OncoArray data: the European Community’s Seventh Framework Programme under grant agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (NIH) (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Personalized Risk Stratification for Prevention and Early Detection of Breast Cancer (PERSPECTIVE) and PERSPECTIVE I&I projects were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation and the Ontario Research Fund. Breast Cancer Family Registry (BCFR): UM1 CA164920 from the National Cancer Institute (NCI). Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. Beth Israel Deaconess Medical Center (BIDMC): Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA): Cancer Association of South Africa (PI Elizabeth J. van Rensburg). Spanish National Cancer Centre (CNIO): Spanish Ministry of Health PI16/00440 supported by Fondo Europeo de Desarrollo Regional (FEDER) funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). City of Hope - Clinical Cancer Genomics Community Research Network (COH-CCGCRN): Research reported in this publication was supported by the NCI of the NIH under grant No. R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the NCI and the Office of the Director, NIH. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 No.15547) to P. Radice. Funds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5x1000’) to S. Manoukian. Associazione CAOS Varese to M.G. Tibiletti. AIRC (IG2015 No.16732) to P. Peterlongo. National Centre for Scientific Research Demokritos (DEMOKRITOS): European Union (European Social Fund—ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. German Cancer Research Center (DFKZ): German Cancer Research Center. Epidemiological Study of Familial Breast Cancer (EMBRACE): Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an National Institute for Health Research (NIHR) grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden National Health Service (NHS) Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Fox Chase Cancer Center (FCCC): The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. AKG was in part funded by the NCI (R01 CA214545 and R01 CA140323), The Kansas Institute for Precision Medicine (P20 GM130423), and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. is the Chancellors Distinguished Chair in Biomedical Sciences Professor. Fundación Pública Galega de Medicina Xenómica (FPGMX): FISPI05/2275 and Mutua Madrileña Foundation (FMMA). German Familial Breast Group (GC-HBOC): German Cancer Aid (grant No. 110837, Rita K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE—Leipzig Research Centre for Civilization Diseases, project No. 713-241202, No. 713-241202, No. 14505/2470, and No. 14575/2470). Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and the French National Institute of Cancer (INCa grants 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015). Georgetown University (GEORGETOWN): the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. Ghent University Hospital (G-FAST): Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. Hospital Clinico San Carlos (HCSC): Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Helsinki Breast Cancer Study (HEBCS): Helsinki University Hospital Research Fund, the Finnish Cancer Society and the Sigrid Juselius Foundation. Hereditary Breast and Ovarian cancer study the Netherlands (HEBON): the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for part of the data collection. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health1R 03CA130065, and North California Cancer Center. Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary (HUNBOCS): Hungarian Research Grants KTIA-OTKA CK-80745 and NKFI_OTKA K-112228. Institut Català d’Oncologia (ICO): The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “FEDER, una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563 and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). International Hereditary Cancer Centre (IHCC): PBZ_KBN_122/P05/2004. Iceland Landspitali – University Hospital (ILUH): Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program—grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade—grant No. PSR-SIIRI-701. Istituto Oncologico Veneto (IOVHBOCS): Ministero della Salute and “5x1000” Istituto Oncologico Veneto grant. Portuguese Oncology Institute-Porto Breast Cancer Study (IPOBCS): Liga Portuguesa Contra o Cancro. Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Korean Hereditary Breast Cancer Study (KOHBRA): the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 1020350; 1420190). Mayo Clinic (MAYO): NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. McGill University (MCGILL): Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Marc Tischkowitz is supported by the funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). Modifier Study of Quantitative Effects on Disease (MODSQUAD): MH CZ—DRO (MMCI, 00209805), MEYS—NPS I—LO1413 to LF, and by Charles University in Prague project UNCE204024 (MZ). Memorial Sloane Kettering Cancer Center (MSKCC): the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). Women’s College Research Institute Hereditary Breast and Ovarian Cancer Study (NAROD): 1R01 CA149429-01. National Cancer Institute (NCI): the Intramural Research Program of the US NCI, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. National Israeli Cancer Control Center (NICCC): Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N.N. Petrov Institute of Oncology (NNPIO): the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. The Ohio State University Comprehensive Cancer Center (OSUCCG): Ohio State University Comprehensive Cancer Center. Università di Pisa (PBCS): AIRC [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. South East Asian Breast Cancer Association Study (SEABASS): Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): the Israeli Cancer Association. Swedish Breast Cancer Study (SWE-BRCA): the Swedish Cancer Society. University of Chicago (UCHICAGO): NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an American Cancer Society (ACS) Clinical Research Professor. University of California Los Angeles (UCLA): Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. University of California San Francisco (UCSF): UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UK Familial Ovarian Cancer Registry (UKFOCR): Cancer Research UK. University of Pennsylvania (UPENN): NIH (R01-CA102776 and R01-CA083855); Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. Cancer Family Registry University of Pittsburg (UPITT/MWH): Hackers for Hope Pittsburgh. Victorian Familial Cancer Trials Group (VFCTG): Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. Women’s Cancer Program at Cedars-Sinai Medical Center (WCP): Dr Karlan is funded by the ACS Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. TN-D is a recipient of a Career Development Fellow from the National Breast Cancer Foundation (Australia, ECF-17-001).

Published
2022
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11. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

Author

Elena Vigorito, Karoline B Kuchenbaecker, Jonathan Beesley, Julian Adlard, Bjarni A Agnarsson, Irene L Andrulis, Banu K Arun, Laure Barjhoux, Muriel Belotti, Javier Benitez, Andreas Berger, Anders Bojesen, Bernardo Bonanni, Carole Brewer, Trinidad Caldes, Maria A Caligo, Ian Campbell, Salina B Chan, Kathleen B M Claes, David E Cohn, Jackie Cook, Mary B Daly, Francesca Damiola, Rosemarie Davidson, Antoine de Pauw, Capucine Delnatte, Orland Diez, Susan M Domchek, Martine Dumont, Katarzyna Durda, Bernd Dworniczak, Douglas F Easton, Diana Eccles, Christina Edwinsdotter Ardnor, Ros Eeles, Bent Ejlertsen, Steve Ellis, D Gareth Evans, Lidia Feliubadalo, Florentia Fostira, William D Foulkes, Eitan Friedman, Debra Frost, Pragna Gaddam, Patricia A Ganz, Judy Garber, Vanesa Garcia-Barberan, Marion Gauthier-Villars, Andrea Gehrig, Anne-Marie Gerdes, Sophie Giraud, Andrew K Godwin, David E Goldgar, Christopher R Hake, Thomas V O Hansen, Sue Healey, Shirley Hodgson, Frans B L Hogervorst, Claude Houdayer, Peter J Hulick, Evgeny N Imyanitov, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Lauren Jacobs, Anna Jakubowska, Ramunas Janavicius, Katarzyna Jaworska-Bieniek, Uffe Birk Jensen, Esther M John, Joseph Vijai, Beth Y Karlan, Karin Kast, KConFab Investigators, Sofia Khan, Ava Kwong, Yael Laitman, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jan Lubinski, Phuong L Mai, Siranoush Manoukian, Sylvie Mazoyer, Alfons Meindl, Arjen R Mensenkamp, Marco Montagna, Katherine L Nathanson, Susan L Neuhausen, Heli Nevanlinna, Dieter Niederacher, Edith Olah, Olufunmilayo I Olopade, Kai-Ren Ong, Ana Osorio, Sue Kyung Park, Ylva Paulsson-Karlsson, Inge Sokilde Pedersen, Bernard Peissel, Paolo Peterlongo, Georg Pfeiler, Catherine M Phelan, Marion Piedmonte, Bruce Poppe, Miquel Angel Pujana, Paolo Radice, Gad Rennert, Gustavo C Rodriguez, Matti A Rookus, Eric A Ross, Rita Katharina Schmutzler, Jacques Simard, Christian F Singer, Thomas P Slavin, Penny Soucy, Melissa Southey, Doris Steinemann, Dominique Stoppa-Lyonnet, Grzegorz Sukiennicki, Christian Sutter, Csilla I Szabo, Muy-Kheng Tea, Manuel R Teixeira, Soo-Hwang Teo, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Elizabeth J van Rensburg, Liliana Varesco, Raymonda Varon-Mateeva, Athanassios Vratimos, Jeffrey N Weitzel, Lesley McGuffog, Judy Kirk, Amanda Ewart Toland, Ute Hamann, Noralane Lindor, Susan J Ramus, Mark H Greene, Fergus J Couch, Kenneth Offit, Paul D P Pharoah, Georgia Chenevix-Trench, and Antonis C Antoniou

Subjects
Medicine, Science
Abstract

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

Published
2016
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12. Diagnostic chest X-rays and breast cancer risk among women with a hereditary predisposition to breast cancer unexplained by a BRCA1 or BRCA2 mutation

Author

Michel Longy, Christine Maugard, Elisabeth Luporsi, Capucine Delnatte, Séverine Eon-Marchais, Marion Gauthier-Villars, Juana Beauvallet, Noura Mebirouk, Muriel Belotti, Alain Lortholary, Sophie Lejeune-Dumoulin, Christine Lasset, Isabelle Mortemousque, Yves-Jean Bignon, François Eisinger, Sylvie Mazoyer, Valérie Bonadona, Jean-Marc Limacher, Anne Tardivon, Paul Gesta, Sandra Fert-Ferrer, Fabienne Lesueur, Dorothée Le Gal, Jean Chiesa, Florent Soubrier, Pascaline Berthet, Laurence Faivre, Bruno Buecher, Nadine Andrieu, Juliette Coignard, Julie Tinat, Thierry Frebourg, Isabelle Coupier, Sophie Giraud, Laure Barjhoux, Catherine Noguès, Séverine Audebert-Bellanger, Claude Adenis-Lavignasse, Chrystelle Colas, Maximiliano Ribeiro Guerra, Laurence Venat-Bouvet, Eve Cavaciuti, Anne Floquet, Pascal Pujol, Francesca Damiola, Anne Fajac, Jean-Pierre Fricker, Hélène Dreyfus, Dominique Stoppa-Lyonnet, Marie-Gabrielle Dondon, Laurence Gladieff, Olivier Caron, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Federal University of Juiz de Fora (UFIJ), Institut Gustave Roussy (IGR), AP-HP. Université Paris Saclay, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Catherine-de-Sienne [Nantes] (CCS), Centre Paul Strauss, CRLCC Paul Strauss, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Hôpital de Mercy, Centre René Gauducheau, CRLCC René Gauducheau, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Bergonié [Bordeaux], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Ramsay Générale de Santé - Hôpital Privé La Louvière, Hôpital Dupuytren [CHU Limoges], Institut Sainte Catherine [Avignon], hôpital couple-enfant [CHU Grenoble Alpes], Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Morvan [Brest], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Groupement Hospitalier Lyon-Est (GHE), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Hôpital pasteur [Colmar], Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU de Bordeaux Pellegrin [Bordeaux], Centre Hospitalier Métropole Savoie [Chambéry], Hôpital René HUGUENIN (Saint-Cloud), CHU Rouen, Normandie Université (NU), Hôpital Edouard Herriot [CHU - HCL], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), MINES ParisTech - École nationale supérieure des mines de Paris, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), COLO, Mouniati, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Adult, Risk, Oncology, medicine.medical_specialty, DNA Repair, DNA repair, [SDV]Life Sciences [q-bio], Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, X-ray exposure, Logistic regression, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Surgical oncology, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Risk factor, RC254-282, High-risk population, Pregnancy, DNA repair genes, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, Middle Aged, medicine.disease, 3. Good health, Radiography, [SDV] Life Sciences [q-bio], Low dose, 030220 oncology & carcinogenesis, Mutation, Female, business, Research Article
Abstract

Background Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation. Methods We evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC. Results Chest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure. Conclusion Ever/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene. Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.

Published
2021
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13. Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach

Author

Marie-Noëlle Bonnet-Dupeyron, Helene Dreyfus, Nadia Boutry-Kryza, Cornel Popovici, Laurent Castera, Nancy Uhrhammer, Anthony Laugé, Yves-Jean Bignon, Hélène Delhomelle, Alice Fiévet, Christophe Guy, Noémie Bronnec, Bruno Buecher, Fabienne Prieur, Sophie Demontety, Vincent Goussot, Emmanuelle Mouret-Fourme, Claire Saule, Helene Zattara, Sarah Malsa, Paul Gesta, Cindy Meira, Erell Guillerm, Isabelle Turbiez, Agathe Ricou, Mélanie Léoné, Pierre Vande Perre, Sarab Lizard, Pascaline Berthet, Norbert Lignon, Adrien Buisson, Anne-Marie Birot, Philippe Denizeau, Etienne Rouleau, Odile Cohen-Haguenauer, Veronica Goldbarg, Virginie Moncoutier, Charlotte Benigni, Emmanuelle Barouk-Simonet, Flavie Boulouard, Caroline Jacquot-Sawka, Alice Yvard, Hakima Lallaoui, Veronica Cusin, Angélina Legros, Muriel Belotti, Christine Maugard, Marine Guillaud-Bataille, Jean-Marc Limacher, Marion Gauthier-Villars, Louise Crivelli, Afane Brahimi, Odile Cabaret, Ophelie Bertrand, Michel Longy, Gabrielle Le Guyadec, Doriane Livon, Amelie Bloucard, Dominique Stoppa-Lyonnet, Capucine Delnatte, Caroline Lecerf, Jennifer Carriere, Virginie Guibert, Véronique Mari, Anne-Sophie Allary, Florence Coulet, Françoise Bonnet, Paul Vilquin, Noémie Basset, Khadija Abidallah, Pierre Macquere, Nicolas Derive, Manon Boulaire, Stephanie Chieze-Valéro, Marine Le Mentec, Mathilde Gay-Bellile, Anne-Laure Conoy, Henri Margot, Pierre Devulder, Mathias Schwartz, Isabelle Tennevet, Stéphane Bézieau, Francesca Damiola, Violaine Bourdon, Audrey Mailliez, Zoe Nevière, Nicolas Viellard, Laurence Venat, Antoine De Pauw, Brigitte Bressac-de Paillerets, Agnès Hardouin, Sofiane Lacoste, Sandra Fert-Ferrer, Maud Privat, Helene Larbre, Dominique Vaur, Etienne Muller, Françoise Revillion, Clémentine Legrand, Rosette Lidereau, Laurence Gladieff, Sabine Raad, Jean Chiesa, Diane Molière, Ahmed Bouras, Nicolas Sevenet, Patrick R. Benusiglio, Sophie Giraud, Christine Toulas, Voreak Suybeng, Florine Oca, Tetsuro Noguchi, Catherine Dehainault, Sophie Lejeune, Céline Heude, Catherine Dubois d’Enghein, Thien-vu Nguyen Minh Tuan, Olivier Caron, Mathilde Warcoin, Christine Lasset, Claude Houdayer, Jessica Moretta-Serra, Julie Tinat, Hagay Sobol, Natalie Jones, Fanny Brayotel, Anne Fajac, Virginie Bubien, Maud Blanluet, Jean-Marc Rey, Anne Durlach, Sandrine M. Caputo, Isabelle Coupier, Fatoumata Simaga, Sophie Krieger, Catherine Noguès, Fabrice Airaud, Robin Fouillet, Celine Garrec, Valérie Bonadona, Julie Menjard, Bérengère Legendre, Chrystelle Colas, Christelle Berthemin, Camille Cohen, Caroline Abadie, Olivier Ingster, Audrey Remenieras, Anaïs Dupré, Jessica Le Gall, Lisa Golmard, Marie Bidart, Henrique Tenreiro, J Bombled, Marie-Charlotte Villy, Marie-Agnès Collonge-Rame, Sophie Dussart, Alain Lortholary, Lucie Salle, Samira Fekairi, Service de Génétique Oncologique, Institut Curie [Paris], Université Paris sciences et lettres (PSL), Département de Biologie des Tumeurs, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Références Cancers Rares (PREDIR), INCA, Institut national du cancer [Boulogne] (INCA), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Centre Hospitalier Universitaire de Reims (CHU Reims), dormoy, valerian, Unité fonctionnelle de neurogénétique moléculaire et cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]

Subjects
Cosegregation, Genotype, [SDV]Life Sciences [q-bio], Breast Neoplasms, Biology, Article, 03 medical and health sciences, Likely benign, Genetics, medicine, Humans, Clinical significance, Genetic Predisposition to Disease, Genetic Testing, Uncertain significance, Gene, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), 030304 developmental biology, BRCA2 Protein, Ovarian Neoplasms, 0303 health sciences, Cancer predisposition, BRCA1 Protein, 030305 genetics & heredity, Cancer, Genetic Variation, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Classification methods, Female
Abstract

Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs. The classification method was a multifactorial model combining different associations between VUSs and cancer, including cosegregation data. At this time, among the 653 variants selected, 101 (15%) distinct variants shared by 1,624 families were classified as pathogenic/likely pathogenic or benign/likely benign by the COVAR study. Sixty-six of the 101 (65%) variants classified by COVAR would have remained VUSs without cosegregation data. Of note, among the 34 variants classified as pathogenic by COVAR, 16 remained VUSs or likely pathogenic when following the ACMG/AMP variant classification guidelines. Although the initiation and organization of cosegregation analyses require a considerable effort, the growing number of available genetic tests results in an increasing number of families sharing a particular variant, and thereby increases the power of such analyses. Here we demonstrate that variant cosegregation analyses are a powerful tool for the classification of variants in the BRCA1/2 breast-ovarian cancer predisposition genes.

Published
2021
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14. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Author

Mia M Gaudet, Karoline B Kuchenbaecker, Joseph Vijai, Robert J Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M Dunning, Andrew Lee, Joe Dennis, Sue Healey, Ed Dicks, Penny Soucy, Olga M Sinilnikova, Vernon S Pankratz, Xianshu Wang, Ronald C Eldridge, Daniel C Tessier, Daniel Vincent, Francois Bacot, Frans B L Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet, KConFab Investigators, Paolo Peterlongo, Rita K Schmutzler, Katherine L Nathanson, Marion Piedmonte, Christian F Singer, Mads Thomassen, Ontario Cancer Genetics Network, Thomas v O Hansen, Susan L Neuhausen, Ignacio Blanco, Mark H Greene, Judith Garber, Jeffrey N Weitzel, Irene L Andrulis, David E Goldgar, Emma D'Andrea, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Elizabeth J van Rensburg, Adalgeir Arason, Gad Rennert, Ans M W van den Ouweland, Annemarie H van der Hout, Carolien M Kets, Cora M Aalfs, Juul T Wijnen, Margreet G E M Ausems, HEBON, EMBRACE, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D Gareth Evans, Chris Jacobs, Julian Adlard, Marc Tischkowitz, Mary E Porteous, Francesca Damiola, GEMO Study Collaborators, Lisa Golmard, Laure Barjhoux, Michel Longy, Muriel Belotti, Sandra Fert Ferrer, Sylvie Mazoyer, Amanda B Spurdle, Siranoush Manoukian, Monica Barile, Maurizio Genuardi, Norbert Arnold, Alfons Meindl, Christian Sutter, Barbara Wappenschmidt, Susan M Domchek, Georg Pfeiler, Eitan Friedman, Uffe Birk Jensen, Mark Robson, Sohela Shah, Conxi Lazaro, Phuong L Mai, Javier Benitez, Melissa C Southey, Marjanka K Schmidt, Peter A Fasching, Julian Peto, Manjeet K Humphreys, Qin Wang, Kyriaki Michailidou, Elinor J Sawyer, Barbara Burwinkel, Pascal Guénel, Stig E Bojesen, Roger L Milne, Hermann Brenner, Magdalena Lochmann, GENICA Network, Kristiina Aittomäki, Thilo Dörk, Sara Margolin, Arto Mannermaa, Diether Lambrechts, Jenny Chang-Claude, Paolo Radice, Graham G Giles, Christopher A Haiman, Robert Winqvist, Peter Devillee, Montserrat García-Closas, Nils Schoof, Maartje J Hooning, Angela Cox, Paul D P Pharoah, Anna Jakubowska, Nick Orr, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Per Hall, Fergus J Couch, Jacques Simard, David Altshuler, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, and Kenneth Offit

Subjects
Genetics, QH426-470
Abstract

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Published
2013
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15. The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Author

GEMO Study Collaborators, EMBRACE Collaborators, OCGN Investigators, HEBON Investigators, kConFab Investigators, IMM (Inge) Lakeman, Alexandra J. van den Broek, Juliën A.M. Vos, Daniel R. Barnes, Julian Adlard, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Judith Balmaña, Daniel Barrowdale, Javier Benitez, Ake Borg, Trinidad Caldés, Maria A. Caligo, W.K. (Kuan) Chung, Kathleen B.M. Claes, Emmanuelle Barouk-Simonet, Muriel Belotti, Pascaline Berthet, Yves Jean Bignon, Valérie Bonadona, Brigitte Bressac-de Paillerets, Bruno Buecher, Sandrine Caputo, O (Olivier) Caron, Laurent Castera, Virginie Caux-Moncoutier, Chrystelle Colas, Marie Agnès Collonge-Rame, Isabelle Coupier, Antoine de Pauw, Capucine Delnatte, Camille Elan, Laurence Faivre, Sandra Fert Ferrer, Marion Gauthier-Villars, Paul Gesta, Sophie Giraud, J.M. (Margriet) Collee, CW (Christoph) Engel, M.J. (Maartje) Hooning, B.A.M. (Annette) Heemskerk - Gerritsen, A. (Antoinette) Hollestelle, A. (Agnes) Jager, L.B. (Linetta) Koppert, AG (Mieke) Kriege, A.M.W. (Ans) van den Ouweland, C.H.M. (Carolien) van Deurzen, H.C. (Lena) van Doorn, GEMO Study Collaborators, EMBRACE Collaborators, OCGN Investigators, HEBON Investigators, kConFab Investigators, IMM (Inge) Lakeman, Alexandra J. van den Broek, Juliën A.M. Vos, Daniel R. Barnes, Julian Adlard, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Judith Balmaña, Daniel Barrowdale, Javier Benitez, Ake Borg, Trinidad Caldés, Maria A. Caligo, W.K. (Kuan) Chung, Kathleen B.M. Claes, Emmanuelle Barouk-Simonet, Muriel Belotti, Pascaline Berthet, Yves Jean Bignon, Valérie Bonadona, Brigitte Bressac-de Paillerets, Bruno Buecher, Sandrine Caputo, O (Olivier) Caron, Laurent Castera, Virginie Caux-Moncoutier, Chrystelle Colas, Marie Agnès Collonge-Rame, Isabelle Coupier, Antoine de Pauw, Capucine Delnatte, Camille Elan, Laurence Faivre, Sandra Fert Ferrer, Marion Gauthier-Villars, Paul Gesta, Sophie Giraud, J.M. (Margriet) Collee, CW (Christoph) Engel, M.J. (Maartje) Hooning, B.A.M. (Annette) Heemskerk - Gerritsen, A. (Antoinette) Hollestelle, A. (Agnes) Jager, L.B. (Linetta) Koppert, AG (Mieke) Kriege, A.M.W. (Ans) van den Ouweland, C.H.M. (Carolien) van Deurzen, and H.C. (Lena) van Doorn

Abstract

Purpose: To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313b

Published
2021
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16. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Author

Henriette Roed Nielsen, Judith Balmaña, Anne-Marie Gerdes, Ellen Honisch, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Douglas F. Easton, Linda Steele, Ava Kwong, Sung Won Kim, Bjarni A. Agnarsson, Piera Rizzolo, Angela R. Solano, Mads Thomassen, Johannes Lemke, Grazia Artioli, Heli Nevanlinna, Johanna I. Kiiski, Frans B. L. Hogervorst, Jong Won Lee, Diana Eccles, Mark H. Greene, Marc Tischkowitz, David E. Goldgar, Angela R. Bradbury, Javier Benitez, Marie Navratilova, Dominique Stoppa-Lyonnet, Arjen R. Mensenkamp, Alfons Meindl, Zisun Kim, Nadine Tung, Agnes Jager, Matthew L. Freedman, Ana Osorio, Norbert Arnold, Doris Steinemann, Inge Søkilde Pedersen, Patricia Llovet, Rob B. van der Luijt, Vivek L Patel, Munaza Ahmed, Lidia Moserle, Irene Konstantopoulou, Jackie Cook, Jacques Simard, Joan Brunet, Johanna Rantala, Kai-ren Ong, Carole Brewer, Joe Dennis, Sook-Yee Yoon, Hanne Meijers-Heijboer, Roberta Villa, Katie Snape, Louise Izatt, Ana Peixoto, Susan M. Domchek, Nina Ditsch, D. Gareth Evans, Tara M. Friebel, Sue K. Park, Katherine L. Nathanson, Lenka Foretova, Miguel Angel Pujana, Edith Olah, Hélène Schuster, Raymonda Varon-Mateeva, Silvia Tognazzo, Payal D. Shah, Oskar T. Johannsson, Hans Ehrencrona, Paul Gesta, Ian G. Campbell, Drakoulis Yannoukakos, Mirjam Larsen, Anthony V. D'Amico, Liene Nikitina-Zake, Davide Bondavalli, Valérie Bonadona, Paul A. James, Alan Donaldson, Antonis C. Antoniou, Bernd Auber, Andrew K. Godwin, Denise Molina Gomes, Jihyoun Lee, Laurence Faivre, Almuth Caliebe, Pilar Garre, Siddhartha Yadav, Julika Borde, Pedro Pérez-Segura, Birgitte Bertelsen, Paolo Peterlongo, Michael T. Parsons, John L. Hopper, Bruno Buecher, Goska Leslie, Shan Wang-Gohrke, Amanda B. Spurdle, T.M. Mooij, Juliane Ramser, kConFab Investigators, Lídia Feliubadaló, Susanne E. Boonen, Bernard Peissel, Anna von Wachenfeldt, Timothy R. Rebbeck, Christi J. van Asperen, Víctor Lorca, Estela Carrasco, Elisa Alducci, Ulrike Faust, Karin Kast, Gord Glendon, Saundra S. Buys, Fergus J. Couch, Mariarosaria Calvello, Istvan Bodrogi, Kathryn J. Ruddy, Philipp Wagner, Fabienne Lesueur, Evan L. Busch, Hebon Investigators, Laura Cortesi, Christian F. Singer, Ute Hamann, Giuseppe Damante, Stefania Tommasi, Esther M. John, Jacopo Azzollini, Cristina Zanzottera, Angelica M. Gutierrez-Barrera, Emmanuelle Mouret-Fourme, Claire Saule, Rosa B. Barkardottir, Kristin K. Zorn, Kerstin Rhiem, Uffe Birk Jensen, Mark Pomerantz, Yuan Chun Ding, Alison H. Trainer, Marco Montagna, Vijai Joseph, Domenico Palli, Kwang-Pil Ko, Angel M. Cronin, Susan L. Neuhausen, Dieter Niederacher, Laura Ottini, Angela Toss, Rita K. Schmutzler, Muriel Belotti, Jeffrey N. Weitzel, Caroline M. Seynaeve, Ileana Carnevali, Adalgeir Arason, Rosalind A. Eeles, Annie T W Chu, Florentia Fostira, Greet Wieme, Brita Arver, Charlotte Kvist Lautrup, Christoph Engel, Marion Gauthier-Villars, Daniel Barrowdale, Caroline Maria Rossing, Kenneth Offit, Kathleen Claes, Olufunmilayo I. Olopade, Penny Soucy, Alicia Barroso, Manuel R. Teixeira, Wendy K. Chung, Gero Kramer, Tsun Leung Chan, Agostina Stradella, Debra Frost, Noura Mebirouk, Liselotte P. van Hest, Esther Darder, Valentina Silvestri, Annabeth Høgh Petersen, Lesley McGuffog, Andrea Gehrig, Mary Porteous, Matti A. Rookus, Lizet E. van der Kolk, Siranoush Manoukian, Lone Sunde, Conxi Lázaro, Maria A. Caligo, Priyanka Sharma, Anne-Bine Skytte, Claus-Eric Ott, Christian Sutter, Paolo Radice, Veronica Medici, Georgia Chenevix-Trench, Vanesa García-Barberán, Kristiina Aittomäki, Amanda E. Toland, Anna Marie Mulligan, Véronique Mari, Bernd Dworniczak, Lynn Martin, Lara Della Puppa, Phuong L. Mai, George Fountzilas, Yen Y. Tan, Simona Agata, Torben A Kruse, Trinidad Caldés, Rosemarie Davidson, Daniel R. Barnes, Thomas Dyrso Jensen, Åke Borg, Mark E. Robson, Jennifer T. Loud, Vivian Y. Shin, Irene López-Perolio, Leigha Senter, Irene L. Andrulis, Rosa Scarpitta, Angela F. Brady, Annika Lindblom, Diana Torres, Lotte Nylandsted Krogh, Barbara Wappenschmidt, Muhammad Rashid, Jeroen Vierstraete, Mary B. Daly, Annelie Liljegren, Frederieke H. van der Baan, Eunyoung Kang, Alessandra Viel, Santiago Cabezas-Camarero, Eric Hahnen, Laura Matricardi, Marinus J. Blok, Edmond S. K. Ma, Maria Grazia Tibiletti, Catarina Santos, Julian Adlard, Soo Hwang Teo, Giuseppe Giannini, Jan Hauke, Peter J. Hulick, Miguel de la Hoya, Clare Miller, Bernardo Bonanni, Bent Ejlertsen, Lajos Géczi, Liliana Varesco, Orland Diez, N Herold, Christine Lasset, Adrià López-Fernández, Min Hyuk Lee, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Clinicum, Department of Obstetrics and Gynecology, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Medical Oncology, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Leslie, Goska [0000-0001-5756-6222], Adlard, Julian [0000-0002-1693-0435], Arnold, Norbert [0000-0003-4523-8808], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Barnes, Daniel R [0000-0002-3781-7570], Brunet, Joan [0000-0003-1945-3512], Caligo, Maria A [0000-0003-0589-1829], Campbell, Ian G [0000-0002-7773-4155], Claes, Kathleen BM [0000-0003-0841-7372], Darder, Esther [0000-0002-7764-1397], Dennis, Joe [0000-0003-4591-1214], Dworniczak, Bernd [0000-0003-4981-7903], Eeles, Rosalind A [0000-0002-3698-6241], Ehrencrona, Hans [0000-0002-5589-3622], Ejlertsen, Bent [0000-0001-8761-714X], Evans, D Gareth [0000-0002-8482-5784], Garre, Pilar [0000-0001-8285-4138], Greene, Mark H [0000-0003-1852-9239], Hulick, Peter J [0000-0001-8397-4078], Jager, Agnes [0000-0002-7713-1450], James, Paul [0000-0002-4361-4657], John, Esther M [0000-0003-3259-8003], Joseph, Vijai [0000-0002-7933-151X], Kim, Sung-Won [0000-0002-1413-2800], Kim, Zisun [0000-0002-1413-2800], Konstantopoulou, Irene [0000-0002-0470-0309], Lesueur, Fabienne [0000-0001-7404-4549], Matricardi, Laura [0000-0002-0241-1810], Gomes, Denise Molina [0000-0002-2836-9008], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Palli, Domenico [0000-0002-5558-2437], Park, Sue K [0000-0001-5002-9707], Parsons, Michael T [0000-0003-3242-8477], Peterlongo, Paolo [0000-0001-6951-6855], Petersen, Annabeth Høgh [0000-0002-4503-6942], Pujana, Miguel Angel [0000-0003-3222-4044], Ruddy, Kathryn J [0000-0001-6298-332X], Scarpitta, Rosa [0000-0001-7590-3827], Shah, Payal D [0000-0001-5874-3390], Silvestri, Valentina [0000-0003-0712-9379], Southey, Melissa C [0000-0002-6313-9005], Spurdle, Amanda B [0000-0003-1337-7897], Stoppa-Lyonnet, Dominique [0000-0002-5438-8309], Sunde, Lone [0000-0002-8479-165X], Teixeira, Manuel R [0000-0002-4896-5982], Teo, Soo Hwang [0000-0002-0444-590X], Tommasi, Stefania [0000-0002-2157-2978], Toss, Angela [0000-0002-1854-6701], van der Luijt, Rob B [0000-0002-0018-1089], Vierstraete, Jeroen [0000-0001-7909-6620], Wieme, Greet [0000-0003-2718-5300], Yadav, Siddhartha [0000-0003-4630-9903], Antoniou, Antonis C [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, and CCA - Cancer biology and immunology

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, endocrine system diseases, PHENOTYPE, INCREASE, Prostate cancer, 0302 clinical medicine, Risk Factors, Young adult, skin and connective tissue diseases, Aged, 80 and over, Prostate cancer risk, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], MESSENGER-RNA DECAY, BRCA1 Protein, Genomics, GERMLINE MUTATIONS, Middle Aged, Prognosis, OVARIAN, CARRIERS, 3. Good health, 030220 oncology & carcinogenesis, Adult, Heterozygote, medicine.medical_specialty, Adolescent, Tumor suppressor gene, Urology, Association (object-oriented programming), 3122 Cancers, MEDLINE, Article, Young Adult, 03 medical and health sciences, Breast cancer, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, BRCA1, BRCA2, Prostate Cancer, Pathogenic sequence variant location, Risk estimation, Journal Article, Genetic predisposition, medicine, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Risk factor, Genetic Association Studies, Aged, BRCA2 Protein, IDENTIFICATION, business.industry, Prostatic Neoplasms, medicine.disease, GENE, Confidence interval, APC, 030104 developmental biology, Mutation, 3111 Biomedicine, business
Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Published
2020
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17. Association of Genomic Domains in

Author

Vivek L, Patel, Evan L, Busch, Tara M, Friebel, Angel, Cronin, Goska, Leslie, Lesley, McGuffog, Julian, Adlard, Simona, Agata, Bjarni A, Agnarsson, Munaza, Ahmed, Kristiina, Aittomäki, Elisa, Alducci, Irene L, Andrulis, Adalgeir, Arason, Norbert, Arnold, Grazia, Artioli, Brita, Arver, Bernd, Auber, Jacopo, Azzollini, Judith, Balmaña, Rosa B, Barkardottir, Daniel R, Barnes, Alicia, Barroso, Daniel, Barrowdale, Muriel, Belotti, Javier, Benitez, Birgitte, Bertelsen, Marinus J, Blok, Istvan, Bodrogi, Valérie, Bonadona, Bernardo, Bonanni, Davide, Bondavalli, Susanne E, Boonen, Julika, Borde, Ake, Borg, Angela R, Bradbury, Angela, Brady, Carole, Brewer, Joan, Brunet, Bruno, Buecher, Saundra S, Buys, Santiago, Cabezas-Camarero, Trinidad, Caldés, Almuth, Caliebe, Maria A, Caligo, Mariarosaria, Calvello, Ian G, Campbell, Ileana, Carnevali, Estela, Carrasco, Tsun L, Chan, Annie T W, Chu, Wendy K, Chung, Kathleen B M, Claes, Gemo Study, Collaborators, Embrace, Collaborators, Jackie, Cook, Laura, Cortesi, Fergus J, Couch, Mary B, Daly, Giuseppe, Damante, Esther, Darder, Rosemarie, Davidson, Miguel, de la Hoya, Lara Della, Puppa, Joe, Dennis, Orland, Díez, Yuan Chun, Ding, Nina, Ditsch, Susan M, Domchek, Alan, Donaldson, Bernd, Dworniczak, Douglas F, Easton, Diana M, Eccles, Rosalind A, Eeles, Hans, Ehrencrona, Bent, Ejlertsen, Christoph, Engel, D Gareth, Evans, Laurence, Faivre, Ulrike, Faust, Lídia, Feliubadaló, Lenka, Foretova, Florentia, Fostira, George, Fountzilas, Debra, Frost, Vanesa, García-Barberán, Pilar, Garre, Marion, Gauthier-Villars, Lajos, Géczi, Andrea, Gehrig, Anne-Marie, Gerdes, Paul, Gesta, Giuseppe, Giannini, Gord, Glendon, Andrew K, Godwin, David E, Goldgar, Mark H, Greene, Angelica M, Gutierrez-Barrera, Eric, Hahnen, Ute, Hamann, Jan, Hauke, Natalie, Herold, Frans B L, Hogervorst, Ellen, Honisch, John L, Hopper, Peter J, Hulick, KConFab, Investigators, Hebon, Investigators, Louise, Izatt, Agnes, Jager, Paul, James, Ramunas, Janavicius, Uffe Birk, Jensen, Thomas Dyrso, Jensen, Oskar Th, Johannsson, Esther M, John, Vijai, Joseph, Eunyoung, Kang, Karin, Kast, Johanna I, Kiiski, Sung-Won, Kim, Zisun, Kim, Kwang-Pil, Ko, Irene, Konstantopoulou, Gero, Kramer, Lotte, Krogh, Torben A, Kruse, Ava, Kwong, Mirjam, Larsen, Christine, Lasset, Charlotte, Lautrup, Conxi, Lazaro, Jihyoun, Lee, Jong Won, Lee, Min Hyuk, Lee, Johannes, Lemke, Fabienne, Lesueur, Annelie, Liljegren, Annika, Lindblom, Patricia, Llovet, Adria, Lopez-Fernández, Irene, Lopez-Perolio, Victor, Lorca, Jennifer T, Loud, Edmond S K, Ma, Phuong L, Mai, Siranoush, Manoukian, Veronique, Mari, Lynn, Martin, Laura, Matricardi, Noura, Mebirouk, Veronica, Medici, Hanne E J, Meijers-Heijboer, Alfons, Meindl, Arjen R, Mensenkamp, Clare, Miller, Denise Molina, Gomes, Marco, Montagna, Thea M, Mooij, Lidia, Moserle, Emmanuelle, Mouret-Fourme, Anna Marie, Mulligan, Katherine L, Nathanson, Marie, Navratilova, Heli, Nevanlinna, Dieter, Niederacher, Finn C Cilius, Nielsen, Liene, Nikitina-Zake, Kenneth, Offit, Edith, Olah, Olufunmilayo I, Olopade, Kai-Ren, Ong, Ana, Osorio, Claus-Eric, Ott, Domenico, Palli, Sue K, Park, Michael T, Parsons, Inge Sokilde, Pedersen, Bernard, Peissel, Ana, Peixoto, Pedro, Pérez-Segura, Paolo, Peterlongo, Annabeth Høgh, Petersen, Mary E, Porteous, Miguel Angel, Pujana, Paolo, Radice, Juliane, Ramser, Johanna, Rantala, Muhammad U, Rashid, Kerstin, Rhiem, Piera, Rizzolo, Mark E, Robson, Matti A, Rookus, Caroline M, Rossing, Kathryn J, Ruddy, Catarina, Santos, Claire, Saule, Rosa, Scarpitta, Rita K, Schmutzler, Hélène, Schuster, Leigha, Senter, Caroline M, Seynaeve, Payal D, Shah, Priyanka, Sharma, Vivian Y, Shin, Valentina, Silvestri, Jacques, Simard, Christian F, Singer, Anne-Bine, Skytte, Katie, Snape, Angela R, Solano, Penny, Soucy, Melissa C, Southey, Amanda B, Spurdle, Linda, Steele, Doris, Steinemann, Dominique, Stoppa-Lyonnet, Agostina, Stradella, Lone, Sunde, Christian, Sutter, Yen Y, Tan, Manuel R, Teixeira, Soo Hwang, Teo, Mads, Thomassen, Maria Grazia, Tibiletti, Marc, Tischkowitz, Silvia, Tognazzo, Amanda E, Toland, Stefania, Tommasi, Diana, Torres, Angela, Toss, Alison H, Trainer, Nadine, Tung, Christi J, van Asperen, Frederieke H, van der Baan, Lizet E, van der Kolk, Rob B, van der Luijt, Liselotte P, van Hest, Liliana, Varesco, Raymonda, Varon-Mateeva, Alessandra, Viel, Jeroen, Vierstraete, Roberta, Villa, Anna, von Wachenfeldt, Philipp, Wagner, Shan, Wang-Gohrke, Barbara, Wappenschmidt, Jeffrey N, Weitzel, Greet, Wieme, Siddhartha, Yadav, Drakoulis, Yannoukakos, Sook-Yee, Yoon, Cristina, Zanzottera, Kristin K, Zorn, Anthony V, D'Amico, Matthew L, Freedman, Mark M, Pomerantz, Georgia, Chenevix-Trench, Antonis C, Antoniou, Susan L, Neuhausen, Laura, Ottini, Henriette Roed, Nielsen, and Timothy R, Rebbeck

Subjects
Adult, Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, Adolescent, BRCA1 Protein, Prostatic Neoplasms, Genomics, Middle Aged, Prognosis, Young Adult, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged
Abstract

Pathogenic sequence variants (PSV) in

Published
2019

18. Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

Author

Caroline Seynaeve, Katja Harbst, Eric A. Ross, Nandita Mitra, Elisa Alducci, Marco Montagna, Janusz Menkiszak, Marion Gauthier-Villars, Javier Benitez, Carole Brewer, Etienne Rouleau, Inge Søkilde Pedersen, Orland Diez, Anya Kushnir, Antonis C. Antoniou, Christine Rappaport, Florentia Fostira, Maurizio Genuardi, Simona Agata, Mark H. Greene, Mary Beth Terry, Nicola Dikow, David E. Goldgar, Anna Jakubowska, Min Hyuk Lee, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Anne-Marie Gerdes, Alexander Miron, Laima Tihomirova, Alan Donaldson, Adalgeir Arason, Rosalind A. Eeles, Fergus J. Couch, Hans Jörg Plendl, Francesca Vignolo-Lutati, Ute Hamann, Jackie Cook, Torben A Kruse, Shani Paluch-Shimon, Lisa Walker, Doris Steinemann, Dorothea Gadzicki, Juul T. Wijnen, Markus C. Fleisch, Kenneth Offit, Mary B. Daly, Jamal Zidan, Georgia Chenevix-Trench, Stephanie V. Blank, Marc Tischkowitz, Esther Darder, Annette Fontaine, Louise Izatt, Elżbieta Złowocka-Perłowska, Nadia Boutry-Kryza, Frans B. L. Hogervorst, Stefanie Engert, Danièle Muller, Susan M. Domchek, Phuong L. Mai, Senno Verhoef, Bernhard H. F. Weber, Cecilia M. Dorfling, Kathleen Claes, Kristiina Aittomäki, Annemarie H. van der Hout, Sharon Sand, Olufunmilayo I. Olopade, Margreet G. E. M. Ausems, Aleksandra Tołoczko-Grabarek, Trevor Cole, Giulietta Scuvera, Ana Osorio, Niklas Loman, Timothy R. Rebbeck, Riccardo Dolcetti, Marit Beer, Harsh B. Pathak, Douglas F. Easton, Lone Sunde, Conxi Lázaro, Raanan Berger, Paolo Radice, Mads Thomassen, Ignacio Blanco, Joseph Vijai, Kristie Bobolis, János Papp, Jean-Pierre Fricker, Christine Walsh, Patricia A. Ganz, Marie Stenmark-Askmalm, Andrea Gehrig, Vernon S. Pankratz, Atocha Romero, Xianshu Wang, Loris Bernard, Viviana Gismondi, Mary Porteous, Muy-Kheng Tea, Karen H. Lu, Gustavo C. Rodriguez, Bernardo Bonanni, Christoph Mundhenke, Julian Adlard, Bent Ejlertsen, Dominique Stoppa-Lyonnet, Nadine Tung, Patrick J. Morrison, Dezheng Huo, Cezary Cybulski, Jack Basil, Georg Pfeiler, Daphne Gschwantler-Kaulich, Heli Nevanlinna, Anders Bojesen, Marion Piedmonte, Katherine L. Nathanson, Amanda E. Toland, Sung-Won Kim, Judy Garber, Amanda B. Spurdle, Noralane M. Lindor, Sanne Traasdahl Moeller, Hans Ehrencrona, Trinidad Caldés, Rosemarie Davidson, Karin Kast, Jenny Lester, Shan Wang-Gohrke, Norbert Arnold, Ana Peixoto, Christine Lasset, Andreas Berger, Olga M. Sinilnikova, Katie Wakely, Claude Houdayer, Mercedes Durán, Robert L. Nussbaum, Ramūnas Janavičius, Christina G. Selkirk, Paolo Aretini, Nina Ditsch, J. Margriet Collée, Rosa B. Barkardottir, Sue Healey, Tomasz Huzarski, Cora M. Aalfs, Gillian Mitchell, Peter J. Hulick, Encarna B. Gomez Garcia, Zakaria Einbeigi, Christian F. Singer, Leigha Senter, Yuan Chun Ding, Dieter Niederacher, Yael Laitman, Siranoush Manoukian, Christoph Engel, Anne De Paepe, Anneliese Fink-Retter, Irene L. Andrulis, Rachel Laframboise, Maria A. Caligo, Priyanka Sharma, Miguel de la Hoya, Teresa Ramón y Cajal, Bruce Poppe, Thomas Hansen, Francesca Damiola, Anne-Bine Skytte, Susan L. Neuhausen, Christian Sutter, Marie-Agnès Collonge-Rame, Johannes J. P. Gille, Barbara Pasini, Wendy K. Chung, Noah D. Kauff, M. John Kennedy, Diana Torres, Salina B. Chan, Mark E. Robson, Elizabeth J. van Rensburg, Eric Hahnen, Barbara Wappenschmidt, Grzegorz Sukiennicki, Esther M. John, Rohini Rau-Murthy, Alice S. Whittemore, Kunle Odunsi, Masoud Azodi, John F. Boggess, Sue K. Park, Rita K. Schmutzler, Muriel Belotti, Jeffrey N. Weitzel, Simon A. Gayther, Fei Wan, Andrew K. Godwin, Arjen R. Mensenkamp, Daniela Zaffaroni, Jacques Simard, Susan Peock, Soo Hwang Teo, Claus R. Bartram, Evgeny N. Imyanitov, Maria-Isabel Tejada, Giuseppe Giannini, Mónica Salinas, Banu Arun, Jan C. Oosterwijk, Jacek Gronwald, Alexandra Becker, Tara M. Friebel, Lenka Foretova, Catherine Noguès, Muhammad Usman Rashid, Valeria Pensotti, Antonella Savarese, Debra Frost, Beatrice Melin, Drakoulis Yannoukakos, Steve Ellis, Jean-Philippe Peyrat, Hagay Sobol, Kim De Leeneer, Radka Platte, Jan Lubinski, Javier Godino, Lesley McGuffog, Tomasz Byrski, Claudine Isaacs, Johanna Rantala, Kelly-Anne Phillips, Carolien M. Kets, Uffe Birk Jensen, Katarzyna Durda, Linda Steele, Beth Y. Karlan, Ava Kwong, Alfons Meindl, Lucia Guidugli, Raymonda Varon-Mateeva, D. Gareth Evans, Edith Olah, Isabelle Mortemousque, Manuel R. Teixeira, Joyce Seldon, Katarzyna Jaworska-Bieniek, Bernard Peissel, Saundra S. Buys, Peter Devilee, Kerstin Rhiem, Eitan Friedman, RS: GROW - Oncology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Cancer Research UK, National Institutes of Health (US), University of Pennsylvania, Breast Cancer Research Foundation, Human Genetics, Human genetics, and Epidemiology and Data Science

Subjects
endocrine system diseases, Genes, BRCA2, MathematicsofComputing_GENERAL, Genes, BRCA1, cancer risk, Settore MED/03 - GENETICA MEDICA, medicine.disease_cause, MOUSE MODELS, Risk Factors, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Age of Onset, POSITION, skin and connective tissue diseases, Adult, Breast Neoplasms, Female, Heterozygote, Humans, Middle Aged, Nucleotides, Ovarian Neoplasms, Genetic Predisposition to Disease, Mutation, Medicine (all), MESSENGER-RNA DECAY, UNKNOWN CLINICAL-SIGNIFICANCE, BRCA1 and BRCA2 genes, mutation type and position, cancer risk, TheoryofComputation_GENERAL, General Medicine, GERMLINE MUTATIONS, CARRIERS, 3. Good health, SUSCEPTIBILITY GENE, Medical genetics, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], medicine.medical_specialty, PROTEINS, mutation type and position, BRCA1 and BRCA2 genes, DNA-SEQUENCE VARIANTS, Article, REGION, Breast cancer, Germline mutation, medicine, BRCA1 or BRCA2, business.industry, Cancer, Heterozygote advantage, medicine.disease, Cancer research, Age of onset, Ovarian cancer, business
Abstract

CIMBA Consortium et al., PMID: 25849179, [Importance]: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. [Objective]: To identify mutation-specific cancer risks for carriers of BRCA1/2. [Design, Setting, and Participants]: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. [Exposures]: Mutations of BRCA1 or BRCA2. [Main Outcomes and Measures]: Breast and ovarian cancer risks. [Results]: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95%CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95%CI, 0.44-0.60; P = 6 × 10-17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95%CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. [Conclusions and Relevance]: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations., Dr Antoniou and the CIMBA data management are funded by Cancer Research UK. Dr Easton is a Principal Research Fellow of Cancer Research UK. Dr Rebbeck is supported by R01-CA083855, R01-CA102776, and P50-CA083638 from the National Institutes of Health (NIH). Dr Rebbeck, Dr Nathanson, Ms Friebel, and Dr Domchek are supported by the Basser Research Center at the University of Pennsylvania. Dr Nathanson is supported by the Breast Cancer Research Foundation. Drs Domchek and Nathanson are supported by the Rooney Family Foundation. Dr Poppe is supported by R01-CA112520 from NIH. Cancer Research UK provided financial support for this work. Dr Antoniou is a Senior Cancer Research UK Cancer Research Fellow. Dr Phillips is a National Breast Cancer Foundation (Australia) Practitioner Fellow.

Published
2015
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19. GENESIS: a French national resource to study the missing heritability of breast cancer

Author

Sylvie Mazoyer, Valérie Layet, Carole Verny-Pierre, Claude Adenis, Marie-Gabrielle Dondon, Isabelle Mortemousque, Morgane Marcou, Olga M. Sinilnikova, Philippe Jonveaux, Anne Floquet, François Eisinger, Yves-Jean Bignon, Catherine Noguès, Laurence Gladieff, Capucine Delnatte, Olivier Caron, Bruno Buecher, Pascaline Berthet, Anne Fajac, Clotilde Penet, Séverine Eon-Marchais, Sandra Fert-Ferrer, Florent Soubrier, Dominique Stoppa-Lyonnet, Chrystelle Colas, Isabelle Coupier, Christine Lasset, Emmanuelle Barouk-Simonet, Michel Longy, Jean-Pierre Fricker, Jean Chiesa, Sophie Giraud, Dominique Leroux, Catherine Dugast, Sophie Lejeune-Dumoulin, Hélène Dreyfus, Annie Chevrier, Odile Cohen-Haguenauer, Thierry Frebourg, Liliane Demange, Julie Tinat, Fabienne Lesueur, Pascal Pujol, Emmanuelle Mouret-Fourme, Elisabeth Luporsi, Christine Maugard, Dorothée Le Gal, Noura Mebirouk, Séverine Audebert-Bellanger, Laure Barjhoux, Muriel Belotti, Eve Cavaciuti, Marion Gauthier-Villars, Marie-Agnès Collonge-Rame, Paul Gesta, Jean-Marc Limacher, Odile Bera, Lucie Toulemonde, Anne Tardivon, Fabienne Prieur, Laurence Faivre, Juana Beauvallet, Alain Lortholary, Nadine Andrieu, François Cornelis, Marc Frenay, Valérie Sornin, Laurence Venat-Bouvet, Francesca Damiola, Valérie Bonadona, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Service de génétique, Institut Curie Paris, Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Catherine-de-Sienne [Nantes] (CCS), CRLCC Eugène Marquis (CRLCC), Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), CRLCC Paul Strauss, CRLCC René Huguenin, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'oncogénétique [Centre georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), CRLCC René Gauducheau, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Bergonié [Bordeaux], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Polyclinique de Courlancy, Institut Sainte Catherine [Avignon], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Claudius Regaud, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Jeanne de Flandre [Lille], Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital pasteur [Colmar], Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Métropole Savoie [Chambéry], CRLCC Jean Godinot, Institut du cancer Courlancy-Reims, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Gustave Flaubert, Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Viggo-Petersen, Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), CHU de la Martinique [Fort de France], Institut Curie, Département d'Imagerie Médicale (Curie Institute, Department of Medical Imaging), F-75005 Paris, France., Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), UL, NGERE, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Lille Nord de France (COMUE)-UNICANCER, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Oncology, Cancer Research, [SDV]Life Sciences [q-bio], Genome-wide association study, Identifies 2, Genome-Wide Association, 0302 clinical medicine, Missing heritability problem, Confer Susceptibility, Susceptibility Loci, 10. No inequality, skin and connective tissue diseases, education.field_of_study, medicine.diagnostic_test, BRCA1 Protein, Middle Aged, 16. Peace & justice, 3. Good health, Neoplasm Proteins, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Female, France, Research Article, Adult, Risk, medicine.medical_specialty, Population, Breast Neoplasms, 03 medical and health sciences, Germline mutation, Breast cancer, Internal medicine, medicine, Genetics, Humans, Genetic Predisposition to Disease, Genetic Testing, education, Germ-Line Mutation, Alleles, Genetic testing, Aged, Gynecology, BRCA2 Protein, Common Variants, business.industry, Genetic heterogeneity, Cancer, medicine.disease, 030104 developmental biology, business
Abstract

Background Less than 20 % of familial breast cancer patients who undergo genetic testing for BRCA1 and BRCA2 carry a pathogenic mutation in one of these two genes. The GENESIS (GENE SISter) study was designed to identify new breast cancer susceptibility genes in women attending cancer genetics clinics and with no BRCA1/2 mutation. Methods The study involved the French national network of family cancer clinics. It was based on enrichment in genetic factors of the recruited population through case selection relying on familial criteria, but also on the consideration of environmental factors and endophenotypes like mammary density or tumor characteristics to assess potential genetic heterogeneity. One of the initial aims of GENESIS was to recruit affected sibpairs. Siblings were eligible when index cases and at least one affected sister were diagnosed with infiltrating mammary or ductal adenocarcinoma, with no BRCA1/2 mutation. In addition, unrelated controls and unaffected sisters were recruited. The enrolment of patients, their relatives and their controls, the collection of the clinical, epidemiological, familial and biological data were centralized by a coordinating center. Results Inclusion of participants started in February 2007 and ended in December 2013. A total of 1721 index cases, 826 affected sisters, 599 unaffected sisters and 1419 controls were included. 98 % of participants completed the epidemiological questionnaire, 97 % provided a blood sample, and 76 % were able to provide mammograms. Index cases were on average 59 years old at inclusion, were born in 1950, and were 49.7 years of age at breast cancer diagnosis. The mean age at diagnosis of affected sisters was slightly higher (51.4 years). The representativeness of the control group was verified. Conclusions The size of the study, the availability of biological specimens and the clinical data collection together with the detailed and complete epidemiological questionnaire make this a unique national resource for investigation of the missing heritability of breast cancer, by taking into account environmental and life style factors and stratifying data on endophenotypes to decrease genetic heterogeneity.

Published
2016
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20. Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

Author

Nadine Andrieu, Bruno Buecher, Sylvie Mazoyer, Paul Gesta, Carole Verny-Pierre, Amandine Garcia, Dominique Stoppa-Lyonnet, Monique Buisson, Jean-Pierre Fricker, Chloe Tessereau, Philippe Vennin, Séverine Eon-Marchais, Olga M. Sinilnikova, Marion Gautier-Villars, Laurence Faivre, Catherine Noguès, Valérie Sornin, Isabelle Coupier, Francesca Damiola, Muriel Belotti, Marie-Gabrielle Dondon, Catherine Dugast, Laure Barjhoux, Alain Lortholary, Olivier Caron, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Service de génétique, Institut Curie Paris, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CRLC Oncologie Val d'Aurelle, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Centre Catherine-de-Sienne [Nantes] (CCS), Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), CRLCC Eugène Marquis (CRLCC), CRLCC Paul Strauss, Hôpital d'Enfants, Service de Médecine Nucléaire, Centre Georges-François Leclerc [Dijon] (CGFL), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Financial support for GENESIS was provided by the Ligue Nationale contre le Cancer (three grants: PRE05/DSL, PRE07/DSL, PRE11/NA), the French National Institute of Cancer (Grant INCa n°2008-029/LL-LC) and the comprehensive cancer center SiRIC (Site de Recherche Intégrée sur le Cancer: Grant INCa-DGOS-4654)., Mines Paris - PSL (École nationale supérieure des mines de Paris), Université de Lille-UNICANCER, and Lissalde, Claire

Subjects
0301 basic medicine, Untranslated region, Adult, medicine.medical_specialty, endocrine system diseases, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetic linkage, Molecular genetics, Genetics, medicine, Missense mutation, Humans, skin and connective tissue diseases, Gene, 3' Untranslated Regions, Genetics (clinical), Aged, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, Three prime untranslated region, BRCA1 Protein, Middle Aged, medicine.disease, 3. Good health, MicroRNAs, 030104 developmental biology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, Case-Control Studies, Mutation, MCF-7 Cells, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, HeLa Cells
Abstract

International audience; Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3ʹ-untranslated regions (3ʹ-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1-and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3ʹ-UTR and one in BRCA2 3ʹ-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3ʹ-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3ʹ-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.

Published
2016
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21. Common Genetic Variation at BARD1 Is Not Associated with Breast Cancer Risk in BRCA1 or BRCA2 Mutation Carriers

Author

Maria A. Caligo, Carol Chu, Xianshu Wang, Senno Verhoef, Joanne L. Blum, Bruno Buecher, Amanda B. Spurdle, Theo A. M. van Os, Per Karlsson, Olga M. Sinilnikova, Sue Healey, Hanne Meijers-Heijboer, Georgia Chenevix-Trench, Marinus J. Blok, Timothy R. Rebbeck, Douglas F. Easton, Mary B. Daly, Annelie Liljegren, Margaret Cook, Christina G. Selkirk, Dominique Stoppa-Lyonnet, Mieke Kriege, Nadine Tung, Muriel Belotti, Susan Peock, Fiona Lalloo, Louise Izatt, Mads Thomassen, Henry T. Lynch, Christian F. Singer, Susan M. Domchek, Margreet G. E. M. Ausems, Tomasz Byrski, Olufunmilayo I. Olopade, Noralane M. Lindor, Claudine Isaacs, Katherine L. Nathanson, Gail E. Tomlinson, Clare Oliver, Hans Ehrencrona, Anna Jakubowska, Francine Durocher, Pascal Pujol, Debra Frost, Tuomas Heikkinen, Christine Lasset, Rosemarie Davidson, Jan Lubinski, Marie Agnés Collonge-Rame, Patricia A. Ganz, Nicoline Hoogerbrugge, Fergus J. Couch, Lesley McGuffog, Matti A. Rookus, Heli Nevanlinna, Helena Jernström, Sylvie Mazoyer, Jonathan Beesley, Judy Garber, Diana Eccles, Don M. Conroy, Xiaoqing Chen, Daphne Gschwantler-Kaulich, Tomasz Huzarski, Carole Verny-Pierre, Antonis C. Antoniou, D. Gareth Evans, Louise Marquart, Juul T. Wijnen, Ros Eeles, Peter Devilee, Laure Barjhoux, Fei Wan, Anne Catharine Dressler, Susan L. Neuhausen, Jeff Weitzel, Hélène Dreyfus, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Human Genetics, Human genetics, CCA - Oncogenesis, Genetica & Celbiologie, and RS: GROW - School for Oncology and Reproduction

Subjects
Oncology, medicine.medical_specialty, Heterozygote, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], endocrine system diseases, Genotype, Epidemiology, Ubiquitin-Protein Ligases, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Breast cancer, Risk Factors, Internal medicine, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Germ-Line Mutation, 030304 developmental biology, BRCA2 Protein, 0303 health sciences, Cancer prevention, Hereditary cancer and cancer-related syndromes [ONCOL 1], BRCA1 Protein, Tumor Suppressor Proteins, Haplotype, Cancer, medicine.disease, Prognosis, 3. Good health, Tumor Markers, Biological, 030220 oncology & carcinogenesis, Cancer research, Female, Breast disease, SNP array
Abstract

Background: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies. Methods: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated. Results: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71–1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59–1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk. Conclusion: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers. Impact: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk. Cancer Epidemiol Biomarkers Prev; 20(5); 1032–8. ©2011 AACR.

Published
2011
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22. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers

Author

Valérie Bonadona, Laurence Brugières, Jean-Michel Flaman, Catherine Bonaïti-Pellié, Thierry Frebourg, Stéphanie Baert-Desurmont, Olivier Caron, Camille Charbonnier, Mariette Renaux-Petel, Muriel Belotti, Dominique Stoppa-Lyonnet, Brigitte Bressac-de Paillerets, Gaëlle Bougeard, Pierre Fermey, Julie Tinat, Patrick R. Benusiglio, Marion Gauthier-Villars, Emilie Consolino, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Service de génétique, Institut Curie Paris, Université Paris sciences et lettres (PSL), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut National du Cancer [Boulogne Billancourt] (INC), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie des cancers, and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, Adult, Male, Cancer Research, Pathology, medicine.medical_specialty, Adolescent, Genotype, medicine.disease_cause, Li-Fraumeni Syndrome, Breast cancer, Germline mutation, Internal medicine, medicine, Missense mutation, Humans, Genetic Testing, Age of Onset, ComputingMilieux_MISCELLANEOUS, Germ-Line Mutation, Mutation, business.industry, Sequence Analysis, DNA, medicine.disease, 3. Good health, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Li–Fraumeni syndrome, Choroid plexus, Female, France, Age of onset, Tumor Suppressor Protein p53, business
Abstract

Purpose The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity. Patients and Methods From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation. Results The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations. Conclusion The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.

Published
2015
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23. Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

Author

Mia M, Gaudet, Karoline B, Kuchenbaecker, Joseph, Vijai, Robert J, Klein, Tomas, Kirchhoff, Lesley, McGuffog, Daniel, Barrowdale, Alison M, Dunning, Andrew, Lee, Joe, Dennis, Sue, Healey, Ed, Dicks, Penny, Soucy, Olga M, Sinilnikova, Vernon S, Pankratz, Xianshu, Wang, Ronald C, Eldridge, Daniel C, Tessier, Daniel, Vincent, Francois, Bacot, Frans B L, Hogervorst, Susan, Peock, Dominique, Stoppa-Lyonnet, Paolo, Peterlongo, Rita K, Schmutzler, Katherine L, Nathanson, Marion, Piedmonte, Christian F, Singer, Mads, Thomassen, Thomas v O, Hansen, Susan L, Neuhausen, Ignacio, Blanco, Mark H, Greene, Judith, Garber, Jeffrey N, Weitzel, Irene L, Andrulis, David E, Goldgar, Emma, D'Andrea, Trinidad, Caldes, Heli, Nevanlinna, Ana, Osorio, Elizabeth J, van Rensburg, Adalgeir, Arason, Gad, Rennert, Ans M W, van den Ouweland, Annemarie H, van der Hout, Carolien M, Kets, Cora M, Aalfs, Juul T, Wijnen, Margreet G E M, Ausems, Debra, Frost, Steve, Ellis, Elena, Fineberg, Radka, Platte, D Gareth, Evans, Chris, Jacobs, Julian, Adlard, Marc, Tischkowitz, Mary E, Porteous, Francesca, Damiola, Lisa, Golmard, Laure, Barjhoux, Michel, Longy, Muriel, Belotti, Sandra Fert, Ferrer, Sylvie, Mazoyer, Amanda B, Spurdle, Siranoush, Manoukian, Monica, Barile, Maurizio, Genuardi, Norbert, Arnold, Alfons, Meindl, Christian, Sutter, Barbara, Wappenschmidt, Susan M, Domchek, Georg, Pfeiler, Eitan, Friedman, Uffe Birk, Jensen, Mark, Robson, Sohela, Shah, Conxi, Lazaro, Phuong L, Mai, Javier, Benitez, Melissa C, Southey, Marjanka K, Schmidt, Peter A, Fasching, Julian, Peto, Manjeet K, Humphreys, Qin, Wang, Kyriaki, Michailidou, Elinor J, Sawyer, Barbara, Burwinkel, Pascal, Guénel, Stig E, Bojesen, Roger L, Milne, Hermann, Brenner, Magdalena, Lochmann, Kristiina, Aittomäki, Thilo, Dörk, Sara, Margolin, Arto, Mannermaa, Diether, Lambrechts, Jenny, Chang-Claude, Paolo, Radice, Graham G, Giles, Christopher A, Haiman, Robert, Winqvist, Peter, Devillee, Montserrat, García-Closas, Nils, Schoof, Maartje J, Hooning, Angela, Cox, Paul D P, Pharoah, Anna, Jakubowska, Nick, Orr, Anna, González-Neira, Guillermo, Pita, M Rosario, Alonso, Per, Hall, Fergus J, Couch, Jacques, Simard, David, Altshuler, Douglas F, Easton, Georgia, Chenevix-Trench, Antonis C, Antoniou, and Kenneth, Offit

Subjects
Adult, BRCA2 Protein, Heterozygote, Genotype, BRCA1 Protein, Breast Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Mutation, Genetics, Cancer Genetics, Genome-Wide Association Studies, Humans, Chromosomes, Human, Pair 6, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, Biology, Alleles, Aged, Genome-Wide Association Study, Research Article
Abstract

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer., Author Summary Women who carry BRCA2 mutations have an increased risk of breast cancer that varies widely. To identify common genetic variants that modify the breast cancer risk associated with BRCA2 mutations, we have built upon our previous work in which we examined genetic variants across the genome in relation to breast cancer risk among BRCA2 mutation carriers. Using a custom genotyping platform with 211,155 genetic variants known as single nucleotide polymorphisms (SNPs), we genotyped 3,881 women who had breast cancer and 4,330 women without breast cancer, which represents the largest possible, international collection of BRCA2 mutation carriers. We identified that a SNP located at 6p24 in the genome was associated with lower risk of breast cancer. Importantly, this SNP was not associated with breast cancer in BRCA1 mutation carriers or in a general population of women, indicating that the breast cancer association with this SNP might be specific to BRCA2 mutation carriers. Combining this BRCA2-specific SNP with 13 other breast cancer risk SNPs also known to modify risk in BRCA2 mutation carriers, we were able to derive a risk prediction model that could be useful in helping women with BRCA2 mutations weigh their risk-reduction strategy options.

Published
2012

24. Sex ratio among the offspring of BRCA mutation carriers

Author

Catherine Bonaïti-Pellié, Agnès Chompret, Dominique Stoppa-Lyonnet, Jean Feunteun, Catherine Noguès, Muriel Belotti, and Anne Helbling-Leclerc

Subjects
Genetics, Male, Heterozygote, Offspring, business.industry, BRCA mutation, Genes, BRCA2, Genes, BRCA1, General Medicine, Pedigree, Text mining, Medicine, Humans, Female, Sex Ratio, business, Sex ratio, Germ-Line Mutation
Published
2004

25. Modulation of spatial alternation and anxiety by septal scopolamine systemic diazepam in mice

Author

Barbara Cagniard, Muriel Belotti, Daniel Galey, and Marie-Pierre Mano

Subjects
Male, Clinical Biochemistry, Scopolamine, Muscarinic Antagonists, Anxiety, Toxicology, Biochemistry, Spatial memory, Parasympatholytic, Behavioral Neuroscience, chemistry.chemical_compound, Mice, medicine, Animals, Neurotransmitter, Biological Psychiatry, Pharmacology, Brain Chemistry, Diazepam, Cognitive disorder, Brain, Spontaneous alternation, medicine.disease, Mice, Inbred C57BL, Memory, Short-Term, chemistry, Anti-Anxiety Agents, Anesthesia, Space Perception, Cholinergic, medicine.symptom, Psychology, medicine.drug
Abstract

To investigate the behavioral consequences of benzodiazepines in subjects whose septo-hippocampal cholinergic (ACh) activity was impaired, C57BL/6 mice received an injection of 2.5 μg/0.2 μl of scopolamine into the medial septal area with an IP injection of 0.5 mg/kg of diazepam. The consequences of these treatments administered in combination or alone were evaluated on anxiety measured in an elevated plus-maze and on spontaneous alternation carried out in a T-maze, using two different intertrial intervals (ITI: 5s or 30s). In these conditions, only the combined treatment provoked a decrease of the anxiety level, which was associated with an impairment of spontaneous alternation restricted to the 5s ITI. Because mice were not impaired during the sequential 30s ITI, this seems to rule out the possibility that this alternation deficit resulted from a working memory loss. These results suggest an involvement of a septal ACh–GABA-A/BDZ interaction in the exaggeration of cognitive deficits produced by benzodiazepines in patients characterized by a cholinergic hypofunction.

Published
1998

26. Consequences of selective blockade of septal noradrenergic afferents on anxiety and spatial working memory performance in mice

Author

Daniel Galey and Muriel Belotti

Subjects
Male, Clinical Biochemistry, Central nervous system, Anxiety, Toxicology, Biochemistry, Spatial memory, Behavioral Neuroscience, chemistry.chemical_compound, Mice, Norepinephrine, Postsynaptic potential, Memory, medicine, Animals, Neurotransmitter, Maze Learning, Biological Psychiatry, Pharmacology, Afferent Pathways, Behavior, Animal, Working memory, Antagonist, Septal nuclei, Mice, Inbred C57BL, medicine.anatomical_structure, chemistry, Septal Nuclei, medicine.symptom, Psychology, Adrenergic Fibers, Neuroscience
Abstract

This experiment was designed to investigate the role of septal noradrenergic (NA) afferents in the control of anxiety and spatial working memory. To this end, C57Bl/6 mice were infused bilaterally into the lateral septal nuclei with 500 ng/0.2 microliter of BE 2254, a selective alpha 1 postsynaptic adrenoceptor antagonist. The consequences of this reversible treatment were evaluated 20 min later on the anxiety level measured in an elevated plus-maze and on spatial working memory, evaluated under four different conditions via the learning of a delayed nonmatching to place (DNMTP) rule achieved in an eight-arm radial maze. In these conditions, the BE 2254, as well as the saline-injected control group, showed an elevation of the anxiety level that may be the indirect expression of a nonspecific septal dysfunction induced by the vehicle injection rather than the normal behavioral response produced by the decrease of septal NA activity. This septal dysfunction also impaired spatial working memory but only when mnesic difficulty of the task is increased, suggesting that this impairment expresses a general memory deficit rather than a working memory deficit per se. A lack of spatial working memory deficits in BE 2254 or saline-injected animals was also observed in two other conditions of the behavioral protocol. However, when treatments were applied before the first exposure of animals to the radial maze (exploration session), only the group which received BE 2254 was impaired during the acquisition session for the rule performed 24 h later. This delayed perturbation seems to be linked, at this stage of the learning procedure, to the lack of NA-dependent processes taking place during the exploration session. Taken together, these data suggest that septal NA mechanisms are more essential at initial stage of this learning, when animals process new features of the situation, than during the expression of spatial working memory per se.

Published
1996

27. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers.

Author

Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, Gauthier-Villars M, Stoppa-Lyonnet D, Consolino E, Brugières L, Caron O, Benusiglio PR, Bressac-de Paillerets B, Bonadona V, Bonaïti-Pellié C, Tinat J, Baert-Desurmont S, and Frebourg T

Subjects
Adolescent, Adult, Age of Onset, Female, France epidemiology, Genetic Testing, Genotype, Germ-Line Mutation, Humans, Li-Fraumeni Syndrome epidemiology, Male, Phenotype, Sequence Analysis, DNA, Li-Fraumeni Syndrome genetics, Tumor Suppressor Protein p53 genetics
Abstract

Purpose: The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity., Patients and Methods: From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation., Results: The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations., Conclusion: The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation., (© 2015 by American Society of Clinical Oncology.)

Published
2015
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