Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1347-1361
Number of pages15
JournalJournal of the American Medical Association
Volume313
Issue number13
DOIs
Publication statusPublished - Apr 7 2015

ASJC Scopus subject areas

  • Medicine(all)

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    Rebbeck, T. R., Mitra, N., Wan, F., Sinilnikova, O. M., Healey, S., McGuffog, L., Chenevix-Trench, G., Easton, D. F., Antoniou, A. C., Nathanson, K. L., Laitman, Y., Kushnir, A., Paluch-Shimon, S., Berger, R., Zidan, J., Friedman, E., Ehrencrona, H., Stenmark-Askmalm, M., Einbeigi, Z., ... Andrulis, I. (2015). Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. Journal of the American Medical Association, 313(13), 1347-1361. https://doi.org/10.1001/jama.2014.5985