Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer.
Rebbeck, Timothy R. PhD 1,2; Mitra, Nandita PhD 2; Wan, Fei MS 2; Sinilnikova, Olga M. PhD 3,+; Healey, Sue 4; McGuffog, Lesley 5; Mazoyer, Sylvie PhD 3; Chenevix-Trench, Georgia PhD 4; Easton, Douglas F. PhD 5; Antoniou, Antonis C. PhD 5; Nathanson, Katherine L. MD 1,6; and the CIMBA Consortium; Laitman, Yael MSC 7; Kushnir, Anya MSC 8; Paluch-Shimon, Shani MD 7; Berger, Raanan MD 9; Zidan, Jamal MD 10; Friedman, Eitan MD; PhD 7; Ehrencrona, Hans MD 11,12; Stenmark-Askmalm, Marie MD 13; Einbeigi, Zakaria MD 14; Loman, Niklas MD 11; Harbst, Katja PhD 11; Rantala, Johanna PhD 15; Melin, Beatrice MD; PhD 16; Huo, Dezheng PhD 17; Olopade, Olufunmilayo I. MD 17; Seldon, Joyce MSGC 18; Ganz, Patricia A. MD 18; Nussbaum, Robert L. MD 19; Chan, Salina B. BS 20; Odunsi, Kunle MD; PhD 21; Gayther, Simon A. PhD 22; Domchek, Susan M. MD 1,6; Arun, Banu K. MD 23; Lu, Karen H. MD 23; Mitchell, Gillian MD 24,25; Karlan, Beth Y. MD 26; Walsh, Christine MD 26; Lester, Jenny MPH 26; Godwin, Andrew K. PhD 27; Pathak, Harsh PhD 27; Ross, Eric PhD 28; Daly, Mary B. MD; PhD 29; Whittemore, Alice S. PhD 20; John, Esther M. PhD; MSPH 30; Miron, Alexander PhD 31; Terry, Mary Beth PhD 32; Chung, Wendy K. MD; PhD 33; Goldgar, David E. PhD 34; Buys, Saundra S. MD 35; Janavicius, Ramunas MD; PhD 36; Tihomirova, Laima MD 37; Tung, Nadine MD 38; Dorfling, Cecilia M. PhD 39; van Rensburg, Elizabeth J. PhD 39; Steele, Linda BS 40; Neuhausen, Susan L. PhD 40; Ding, Yuan Chun PhD 40; Ejlertsen, Bent MD; PhD 41; Gerdes, Anne-Marie MD 41; Hansen, Thomas v. O. MD 42; Ramon y Cajal, Teresa MD 43; Osorio, Ana PhD 44; Benitez, Javier MD 45; Godino, Javier MD 46; Tejada, Maria-Isabel PhD 47; Duran, Mercedes PhD 48; Weitzel, Jeffrey N. MD 49; Bobolis, Kristie A MD 49; Sand, Sharon R. CCRP 49; Fontaine, Annette MD 49; Savarese, Antonella MD 50; Pasini, Barbara MD 51; Peissel, Bernard MD 52; Bonanni, Bernardo MD 53; Zaffaroni, Daniela PhD 52; Vignolo-Lutati, Francesca PhD 54; Scuvera, Giulietta MD 52; Giannini, Giuseppe MD 55; Bernard, Loris PhD 56,57; Genuardi, Maurizio MD 58; Radice, Paolo PhD 59,60; Dolcetti, Riccardo MD 61; Manoukian, Siranoush MD 52; Pensotti, Valeria PhD 57,60; Gismondi, Viviana PhD 62; Yannoukakos, Drakoulis PhD 63; Fostira, Florentia PhD 63; Garber, Judy MD; MPH 31; Torres, Diana MD 64,65; Rashid, Muhammad Usman MD 65,66; Hamann, Ute PhD 65; Peock, Susan MS 5; Frost, Debra MS 5; Platte, Radka BS 5; Evans, D. Gareth MD 67; Eeles, Rosalind PhD 68; Davidson, Rosemarie PhD 69; Eccles, Diana MD 70; Cole, Trevor MD 71; Cook, Jackie MD 72; Brewer, Carole MD 73; Hodgson, Shirley MD 74; Morrison, Patrick J. MD; DSc 75; Walker, Lisa MS 76; Porteous, Mary E. MD 77; Kennedy, M. John PhD 78; Izatt, Louise MBBChir; PhD 79; Adlard, Julian MD 80; Donaldson, Alan MD 81; Ellis, Steve MSc 5; Sharma, Priyanka PhD 82; Schmutzler, Rita Katharina MD 83; Wappenschmidt, Barbara MD 83; Becker, Alexandra MD 83; Rhiem, Kerstin MD 83; Hahnen, Eric MD 83; Engel, Christoph MD 84; Meindl, Alfons MD 85; Engert, Stefanie MD 85; Ditsch, Nina MD 85; Arnold, Norbert MD 86; Plendl, Hans Jorg MD 87; Mundhenke, Christoph MD 86; Niederacher, Dieter MD 88; Fleisch, Markus MD 88; Sutter, Christian PhD 89; Bartram, C. R. MD 89; Dikow, Nicola MD 89; Wang-Gohrke, Shan MD 90; Gadzicki, Dorothea MD 91; Steinemann, Doris MD 91; Kast, Karin MD 92; Beer, Marit MD 93; Varon-Mateeva, Raymonda MD 94; Gehrig, Andrea MD 95; Weber, Bernhard H. MD 96; Stoppa-Lyonnet, Dominique PhD 97,98,99; Sinilnikova, Olga M. 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Margriet PhD 125; Seynaeve, Caroline MD; PhD 126; Oosterwijk, Jan C. MD; PhD 123; Gille, Johannes J. P. PhD 127; Wijnen, Juul T. PhD 128; Garcia, Encarna B. Gomez MD 129; Kets, Carolien M. MD 130; Ausems, Margreet G. E. M. MD 131; Aalfs, Cora M. MD 132; Devilee, Peter MD 133; Mensenkamp, Arjen R. PhD 130; Kwong, Ava MD 134,135,136; Olah, Edith PhD; DSc 137; Papp, Janos PhD 137; Diez, Orland PhD 138,139; Lazaro, Conxi PhD 140; Darder, Esther PhD 141; Blanco, Ignacio MD 142; Salinas, Monica MS 142; Jakubowska, Anna PhD 143; Lubinski, Jan MD 143; Gronwald, Jacek PhD 143; Jaworska-Bieniek, Katarzyna PhD 143,144; Durda, Katarzyna PhD 143; Sukiennicki, Grzegorz PhD 143; Huzarski, Tomasz PhD 143; Byrski, Tomasz PhD 143; Cybulski, Cezary PhD 143; Toloczko-Grabarek, Aleksandra PhD 143; Zlowocka-Perlowska, Elzbieta PhD 143; Menkiszak, Janusz ND 145; Arason, Adalgeir ND 146,147; Barkardottir, Rosa B. ND 146,147; Simard, Jacques PhD 148,149; Laframboise, Rachel MD 150,151; Montagna, Marco PhD 151; Agata, Simona PhD 151; Alducci, Elisa PhD 151; Peixoto, Ana PhD 152; Teixeira, Manuel R. MD; PhD 152,153; Spurdle, Amanda B. PhD 4; Lee, Min Hyuk MD 154; Park, Sue K. MD 155; Kim, Sung-Won MD; PhD 156; Friebel, Tara M. MPH 2; Couch, Fergus J. PhD 157,159; Lindor, Noralane M. MD 159; Pankratz, Vernon S. PhD 159; Guidugli, Lucia PhD 157; Wang, Xianshu PhD 157; Tischkowitz, Marc PhD 160,161; Foretova, Lenka MD 162; Vijai, Joseph MD 163; Offit, Kenneth MD 163; Robson, Mark MD 164; Rau-Murthy, Rohini MD 164; Kauff, Noah MD 164; Fink-Retter, Anneliese MD 165; Singer, Christian F. MD 165; Rappaport, Christine MD 165; Gschwantler-Kaulich, Daphne MD 165; Pfeiler, Georg MD 165; Tea, Muy-Kheng MD 165; Berger, Andreas MD 165; Greene, Mark H. MD 166; Mai, Phuong L. PhD 166; Imyanitov, Evgeny N. MD 167; Toland, Amanda Ewart PhD 168; Senter, Leigha MD 169; Bojesen, Anders PhD 170; Pedersen, Inge Sokilde PhD 171; Skytte, Anne-Bine PhD 170; Sunde, Lone PhD 172; Thomassen, Mads PhD 173; Moeller, Sanne Traasdahl PhD 173; Kruse, Torben A. PhD 173; Jensen, Uffe Birk PhD 172; Caligo, Maria Adelaide MD 174; Aretini, Paolo MD 174; Teo, Soo-Hwang PhD 175,176; Selkirk, Christina G. MS; CCRP 177; Hulick, Peter J. MD; MMSc 177; Andrulis, Irene 178
[Article]
JAMA.
313(13):1347-1361, April 7, 2015.
(Format: HTML, PDF)
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 of women who were 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 x 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 x 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 x 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 x 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.
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