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 × 1 0 −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 × 1 0 −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 × 1 0 −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 × 1 0 −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
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