Scholars@Duke publication: Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

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

Publication , Journal Article

Rebbeck, TR; Mitra, N; Wan, F; Sinilnikova, OM; Healey, S; McGuffog, L; Mazoyer, S; Chenevix-Trench, G; Easton, DF; Antoniou, AC; Nathanson, KL ...

Published in: JAMA

April 2015

Published version (DOI)

Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.To identify mutation-specific cancer risks for carriers of BRCA1/2.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.Mutations of BRCA1 or BRCA2.Breast and ovarian cancer risks.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.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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Published In

JAMA

DOI

10.1001/jama.2014.5985

EISSN

1538-3598

ISSN

0098-7484

Publication Date

April 2015

Volume

313

Issue

Start / End Page

1347 / 1361

Related Subject Headings

Risk Factors
Ovarian Neoplasms
Nucleotides
Mutation
Middle Aged
Humans
Heterozygote
Genetic Predisposition to Disease
Genes, BRCA2
Genes, BRCA1

Citation

APA

Chicago

ICMJE

MLA

NLM

Rebbeck, T. R., Mitra, N., Wan, F., Sinilnikova, O. M., Healey, S., McGuffog, L., … Andrulis, I. (2015). Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA, 313(13), 1347–1361. https://doi.org/10.1001/jama.2014.5985

Rebbeck, Timothy R., Nandita Mitra, Fei Wan, Olga M. Sinilnikova, Sue Healey, Lesley McGuffog, Sylvie Mazoyer, et al. “Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.” JAMA 313, no. 13 (April 2015): 1347–61. https://doi.org/10.1001/jama.2014.5985.

Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, McGuffog L, et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA. 2015 Apr;313(13):1347–61.

Rebbeck, Timothy R., et al. “Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.” JAMA, vol. 313, no. 13, Apr. 2015, pp. 1347–61. Epmc, doi:10.1001/jama.2014.5985.

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. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA. 2015 Apr;313(13):1347–1361.

Published In

JAMA

DOI

10.1001/jama.2014.5985

EISSN

1538-3598

ISSN

0098-7484

Publication Date

April 2015

Volume

313

Issue

Start / End Page

1347 / 1361

Related Subject Headings

Risk Factors
Ovarian Neoplasms
Nucleotides
Mutation
Middle Aged
Humans
Heterozygote
Genetic Predisposition to Disease
Genes, BRCA2
Genes, BRCA1