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

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  • Timothy R Rebbeck
  • Nandita Mitra
  • Fei Wan
  • Olga M Sinilnikova
  • Sue Healey
  • Lesley McGuffog
  • Sylvie Mazoyer
  • Georgia Chenevix-Trench
  • Douglas F Easton
  • Antonis C Antoniou
  • Katherine L Nathanson
  • Yael Laitman
  • Anya Kushnir
  • Shani Paluch-Shimon
  • Raanan Berger
  • Jamal Zidan
  • Eitan Friedman
  • Hans Ehrencrona
  • Marie Stenmark-Askmalm
  • Zakaria Einbeigi
  • Niklas Loman
  • Katja Harbst
  • Johanna Rantala
  • Beatrice Melin
  • Dezheng Huo
  • Olufunmilayo I Olopade
  • Joyce Seldon
  • Patricia A Ganz
  • Robert L Nussbaum
  • Salina B Chan
  • Kunle Odunsi
  • Simon A Gayther
  • Susan M Domchek
  • Banu K Arun
  • Karen H Lu
  • Gillian Mitchell
  • Beth Y Karlan
  • Christine Walsh
  • Jenny Lester
  • Andrew K Godwin
  • Harsh Pathak
  • Eric Ross
  • Mary B Daly
  • Alice S Whittemore
  • Esther M John
  • Alexander Miron
  • Mary Beth Terry
  • Bent Ejlertsen
  • Anne-Marie Gerdes
  • Thomas v O Hansen
  • CIMBA Consortium
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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.

Original languageEnglish
JournalJ A M A: The Journal of the American Medical Association
Volume313
Issue number13
Pages (from-to)1347-61
Number of pages15
ISSN0098-7484
DOIs
Publication statusPublished - 7 Apr 2015

    Research areas

  • Adult, Age of Onset, Breast Neoplasms, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Heterozygote, Humans, Middle Aged, Mutation, Nucleotides, Ovarian Neoplasms, Risk Factors

ID: 45843882