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

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

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION（2015）

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摘要

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% Cl, 1.22-1.74; P = 2 x 10(-6)), c.4328 to c.4945 (BCCR2; RH R = 1.34; 95% Cl, 1.01-1.78; P =.04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% Cl, 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% Cl, 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% Cl, 1.06-2.78; P =.03), c.772 to c.1806 (BCCRI; RHR = 1.63; 95% Cl, 1.10-2.40; P =.01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% Cl, 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% Cl, 0.44-0.60; P = 6 x 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% Cl, 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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关键词

nucleotides,risk factors,heterozygote,breast cancer,mutation,risk

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