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

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Journal Article

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 × 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.

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  • Rebbeck, TR; Mitra, N; Wan, F; Sinilnikova, OM; Healey, S; McGuffog, L; Mazoyer, S; Chenevix-Trench, G; Easton, DF; Antoniou, AC; Nathanson, KL; CIMBA Consortium, ; Laitman, Y; Kushnir, A; Paluch-Shimon, S; Berger, R; Zidan, J; Friedman, E; Ehrencrona, H; Stenmark-Askmalm, M; Einbeigi, Z; Loman, N; Harbst, K; Rantala, J; Melin, B; Huo, D; Olopade, OI; Seldon, J; Ganz, PA; Nussbaum, RL; Chan, SB; Odunsi, K; Gayther, SA; Domchek, SM; Arun, BK; Lu, KH; Mitchell, G; Karlan, BY; Walsh, C; Lester, J; Godwin, AK; Pathak, H; Ross, E; Daly, MB; Whittemore, AS; John, EM; Miron, A; Terry, MB; Chung, WK; Goldgar, DE; Buys, SS; Janavicius, R; Tihomirova, L; Tung, N; Dorfling, CM; van Rensburg, EJ; Steele, L; Neuhausen, SL; Ding, YC; Ejlertsen, B; Gerdes, A-M; Hansen, TVO; Ramón y Cajal, T; Osorio, A; Benitez, J; Godino, J; Tejada, M-I; Duran, M; Weitzel, JN; Bobolis, KA; Sand, SR; Fontaine, A; Savarese, A; Pasini, B; Peissel, B; Bonanni, B; Zaffaroni, D; Vignolo-Lutati, F; Scuvera, G; Giannini, G; Bernard, L; Genuardi, M; Radice, P; Dolcetti, R; Manoukian, S; Pensotti, V; Gismondi, V; Yannoukakos, D; Fostira, F; Garber, J; Torres, D; Rashid, MU; Hamann, U; Peock, S; Frost, D; Platte, R; Evans, DG; Eeles, R; Davidson, R; Eccles, D; Cole, T; Cook, J; Brewer, C; Hodgson, S; Morrison, PJ; Walker, L; Porteous, ME; Kennedy, MJ; Izatt, L; Adlard, J; Donaldson, A; Ellis, S; Sharma, P; Schmutzler, RK; Wappenschmidt, B; Becker, A; Rhiem, K; Hahnen, E; Engel, C; Meindl, A; Engert, S; Ditsch, N; Arnold, N; Plendl, HJ; Mundhenke, C; Niederacher, D; Fleisch, M; Sutter, C; Bartram, CR; Dikow, N; Wang-Gohrke, S; Gadzicki, D; Steinemann, D; Kast, K; Beer, M; Varon-Mateeva, R; Gehrig, A; Weber, BH; Stoppa-Lyonnet, D; Houdayer, C; Belotti, M; Gauthier-Villars, M; Damiola, F; Boutry-Kryza, N; Lasset, C; Sobol, H; Peyrat, J-P; Muller, D; Fricker, J-P; Collonge-Rame, M-A; Mortemousque, I; Nogues, C; Rouleau, E; Isaacs, C; De Paepe, A; Poppe, B; Claes, K; De Leeneer, K; Piedmonte, M; Rodriguez, G; Wakely, K; Boggess, J; Blank, SV; Basil, J; Azodi, M; Phillips, K-A; Caldes, T; de la Hoya, M; Romero, A; Nevanlinna, H; Aittomäki, K; van der Hout, AH; Hogervorst, FBL; Verhoef, S; Collée, JM; Seynaeve, C; Oosterwijk, JC; Gille, JJP; Wijnen, JT; Gómez Garcia, EB; Kets, CM; Ausems, MGEM; Aalfs, CM; Devilee, P; Mensenkamp, AR; Kwong, A; Olah, E; Papp, J; Diez, O; Lazaro, C; Darder, E; Blanco, I; Salinas, M; Jakubowska, A; Lubinski, J; Gronwald, J; Jaworska-Bieniek, K; Durda, K; Sukiennicki, G; Huzarski, T; Byrski, T; Cybulski, C; Toloczko-Grabarek, A; Złowocka-Perłowska, E; Menkiszak, J; Arason, A; Barkardottir, RB; Simard, J; Laframboise, R; Montagna, M; Agata, S; Alducci, E; Peixoto, A; Teixeira, MR; Spurdle, AB; Lee, MH; Park, SK; Kim, S-W; Friebel, TM; Couch, FJ; Lindor, NM; Pankratz, VS; Guidugli, L; Wang, X; Tischkowitz, M; Foretova, L; Vijai, J; Offit, K; Robson, M; Rau-Murthy, R; Kauff, N; Fink-Retter, A; Singer, CF; Rappaport, C; Gschwantler-Kaulich, D; Pfeiler, G; Tea, M-K; Berger, A; Greene, MH; Mai, PL; Imyanitov, EN; Toland, AE; Senter, L; Bojesen, A; Pedersen, IS; Skytte, A-B; Sunde, L; Thomassen, M; Moeller, ST; Kruse, TA; Jensen, UB; Caligo, MA; Aretini, P; Teo, S-H; Selkirk, CG; Hulick, PJ; Andrulis, I

Published Date

  • April 2015

Published In

Volume / Issue

  • 313 / 13

Start / End Page

  • 1347 - 1361

PubMed ID

  • 25849179

Pubmed Central ID

  • 25849179

Electronic International Standard Serial Number (EISSN)

  • 1538-3598

International Standard Serial Number (ISSN)

  • 0098-7484

Digital Object Identifier (DOI)

  • 10.1001/jama.2014.5985

Language

  • eng