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

Rebbeck, Tr; Mitra, N; Wan, F; Sinilnikova, Om; Healey, S; Mcguffog, L; Mazoyer, S; Chenevix Trench, G; Easton, Df; Antoniou, Ac; Nathanson, Kl; Consortium, Cimba; 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; Kh, Lu; 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, Am; Hansen, Tv; Cajal T, Ramón y.; Osorio, A; Benitez, J; Godino, J; Tejada, Mi; Duran, M; Weitzel, Jn; Bobolis, Ka; Sand, Sr; Fontaine, A; Savarese, A; Pasini, Barbara; 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; Sinilnikova, Om; Mazoyer, S; Houdayer, C; Belotti, M; Gauthier Villars, M; Damiola, F; Boutry Kryza, N; Lasset, C; Sobol, H; Peyrat, Jp; Muller, D; Fricker, Jp; Collonge Rame MA,; 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, Ka; Caldes, T; de la Hoya, M; Romero, A; Nevanlinna, H; Aittomäki, K; van der Hout AH,; Hogervorst, Fb; Verhoef, S; Collée, Jm; Seynaeve, C; Oosterwijk, Jc; Gille, Jj; Wijnen, Jt; Gómez Garcia EB,; Kets, Cm; Ausems, Mg; 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, Sw; 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, Mk; Berger, A; Greene, Mh; Mai, Pl; Imyanitov, En; Toland, Ae; Senter, L; Bojesen, A; Pedersen, Is; Skytte, Ab; Sunde, L; Thomassen, M; Moeller, St; Kruse, Ta; Jensen, Ub; Caligo, Ma; Aretini, P; Teo, Sh; Selkirk, Cg; Hulick, Pj; Andrulis, I.

doi:10.1001/jama.2014.5985

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.