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JAMA. 2015 Apr 8. pii: 2214084. doi: 10.1001/jama.2014.5985. pmc: PMC4537700. mid: NIHMS693111

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

Rebbeck TR¹, Mitra N², Wan F³, Sinilnikova OM⁴, Healey S⁵, McGuffog L⁶, Mazoyer S⁷, Chenevix-Trench G⁸, Easton DF⁹, Antoniou AC¹⁰, Nathanson KL¹¹, Laitman Y¹², Kushnir A¹³, Paluch-Shimon S¹⁴, Berger R¹⁵, Zidan J¹⁶, Friedman E¹⁷, Ehrencrona H¹⁸, Stenmark-Askmalm M¹⁹, Einbeigi Z²⁰, Loman N²¹, Harbst K²², Rantala J²³, Melin B²⁴, Huo D²⁵, Olopade OI²⁶, Seldon J²⁷, Ganz PA²⁸, Nussbaum RL²⁹, Chan SB³⁰, Odunsi K³¹, Gayther SA³², Domchek SM³³, Arun BK³⁴, Lu KH³⁵, Mitchell G³⁶, Karlan BY³⁷, Walsh C³⁸, Lester J³⁹, Godwin AK⁴⁰, Pathak H⁴¹, Ross E⁴², Daly MB⁴³, Whittemore AS⁴⁴, John EM⁴⁵, Miron A⁴⁶, Terry MB⁴⁷, Chung WK⁴⁸, Goldgar DE⁴⁹, Buys SS⁵⁰, Janavicius R⁵¹, Tihomirova L⁵², Tung N⁵³, Dorfling CM⁵⁴, van Rensburg EJ⁵⁵, Steele L⁵⁶, Neuhausen SL⁵⁷, Ding YC⁵⁸, Ejlertsen B⁵⁹, Gerdes AM⁶⁰, Hansen Tv⁶¹, Ramón y Cajal T⁶², Osorio A⁶³, Benitez J⁶⁴, Godino J⁶⁵, Tejada MI⁶⁶, Duran M⁶⁷, Weitzel JN⁶⁸, Bobolis KA⁶⁹, Sand SR⁷⁰, Fontaine A⁷¹, Savarese A⁷², Pasini B⁷³, Peissel B⁷⁴, Bonanni B⁷⁵, Zaffaroni D⁷⁶, Vignolo-Lutati F⁷⁷, Scuvera G⁷⁸, Giannini G⁷⁹, Bernard L⁸⁰, Genuardi M⁸¹, Radice P⁸², Dolcetti R⁸³, Manoukian S⁸⁴, Pensotti V⁸⁵, Gismondi V⁸⁶, Yannoukakos D⁸⁷, Fostira F⁸⁸, Garber J⁸⁹, Torres D⁹⁰, Rashid MU⁹¹, Hamann U⁹², Peock S⁹³, Frost D⁹⁴, Platte R⁹⁵, Evans DG⁹⁶, Eeles R⁹⁷, Davidson R⁹⁸, Eccles D⁹⁹, Cole T¹⁰⁰, Cook J¹⁰¹, Brewer C¹⁰², Hodgson S¹⁰³, Morrison PJ¹⁰⁴, Walker L¹⁰⁵, Porteous ME¹⁰⁶, Kennedy MJ¹⁰⁷, Izatt L¹⁰⁸, Adlard J¹⁰⁹, Donaldson A¹¹⁰, Ellis S¹¹¹, Sharma P¹¹², Schmutzler RK¹¹³, Wappenschmidt B¹¹⁴, Becker A¹¹⁵, Rhiem K¹¹⁶, Hahnen E¹¹⁷, Engel C¹¹⁸, Meindl A¹¹⁹, Engert S¹²⁰, Ditsch N¹²¹, Arnold N¹²², Plendl HJ¹²³, Mundhenke C¹²⁴, Niederacher D¹²⁵, Fleisch M¹²⁶, Sutter C¹²⁷, Bartram CR¹²⁸, Dikow N¹²⁹, Wang-Gohrke S¹³⁰, Gadzicki D¹³¹, Steinemann D¹³², Kast K¹³³, Beer M¹³⁴, Varon-Mateeva R¹³⁵, Gehrig A¹³⁶, Weber BH¹³⁷, Stoppa-Lyonnet D¹³⁸, Sinilnikova OM¹³⁹, Mazoyer S¹⁴⁰, Houdayer C¹⁴¹, Belotti M¹⁴², Gauthier-Villars M¹⁴³, Damiola F¹⁴⁴, Boutry-Kryza N¹⁴⁵, Lasset C¹⁴⁶, Sobol H¹⁴⁷, Peyrat JP¹⁴⁸, Muller D¹⁴⁹, Fricker JP¹⁵⁰, Collonge-Rame MA¹⁵¹, Mortemousque I¹⁵², Nogues C¹⁵³, Rouleau E¹⁵⁴, Isaacs C¹⁵⁵, De Paepe A¹⁵⁶, Poppe B¹⁵⁷, Claes K¹⁵⁸, De Leeneer K¹⁵⁹, Piedmonte M¹⁶⁰, Rodriguez G¹⁶¹, Wakely K¹⁶², Boggess J¹⁶³, Blank SV¹⁶⁴, Basil J¹⁶⁵, Azodi M¹⁶⁶, Phillips KA¹⁶⁷, Caldes T¹⁶⁸, de la Hoya M¹⁶⁹, Romero A¹⁷⁰, Nevanlinna H¹⁷¹, Aittomäki K¹⁷², van der Hout AH¹⁷³, Hogervorst FB¹⁷⁴, Verhoef S¹⁷⁵, Collée JM¹⁷⁶, Seynaeve C¹⁷⁷, Oosterwijk JC¹⁷⁸, Gille JJ¹⁷⁹, Wijnen JT¹⁸⁰, Gómez Garcia EB¹⁸¹, Kets CM¹⁸², Ausems MG¹⁸³, Aalfs CM¹⁸⁴, Devilee P¹⁸⁵, Mensenkamp AR¹⁸⁶, Kwong A¹⁸⁷, Olah E¹⁸⁸, Papp J¹⁸⁹, Diez O¹⁹⁰, Lazaro C¹⁹¹, Darder E¹⁹², Blanco I¹⁹³, Salinas M¹⁹⁴, Jakubowska A¹⁹⁵, Lubinski J¹⁹⁶, Gronwald J¹⁹⁷, Jaworska-Bieniek K¹⁹⁸, Durda K¹⁹⁹, Sukiennicki G²⁰⁰, Huzarski T²⁰¹, Byrski T²⁰², Cybulski C²⁰³, Toloczko-Grabarek A²⁰⁴, Złowocka-Perłowska E²⁰⁵, Menkiszak J²⁰⁶, Arason A²⁰⁷, Barkardottir RB²⁰⁸, Simard J²⁰⁹, Laframboise R²¹⁰, Montagna M²¹¹, Agata S²¹², Alducci E²¹³, Peixoto A²¹⁴, Teixeira MR²¹⁵, Spurdle AB²¹⁶, Lee MH²¹⁷, Park SK²¹⁸, Kim SW²¹⁹, Friebel TM²²⁰, Couch FJ²²¹, Lindor NM²²², Pankratz VS²²³, Guidugli L²²⁴, Wang X²²⁵, Tischkowitz M²²⁶, Foretova L²²⁷, Vijai J²²⁸, Offit K²²⁹, Robson M²³⁰, Rau-Murthy R²³¹, Kauff N²³², Fink-Retter A²³³, Singer CF²³⁴, Rappaport C²³⁵, Gschwantler-Kaulich D²³⁶, Pfeiler G²³⁷, Tea MK²³⁸, Berger A²³⁹, Greene MH²⁴⁰, Mai PL²⁴¹, Imyanitov EN²⁴², Toland AE²⁴³, Senter L²⁴⁴, Bojesen A²⁴⁵, Pedersen IS²⁴⁶, Skytte AB²⁴⁷, Sunde L²⁴⁸, Thomassen M²⁴⁹, Moeller ST²⁵⁰, Kruse TA²⁵¹, Jensen UB²⁵², Caligo MA²⁵³, Aretini P²⁵⁴, Teo SH²⁵⁵, Selkirk CG²⁵⁶, Hulick PJ²⁵⁷, Andrulis I²⁵⁸

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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 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.

Publikations ID: 25849179
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