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

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
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.Dr Antoniou and the CIMBA
data management are funded by Cancer Research
UK. Dr Easton is a Principal Research Fellow of
Cancer Research UK. Dr Rebbeck is supported by
R01-CA083855, R01-CA102776, and P50-
CA083638 from the National Institutes of Health
(NIH). Dr Rebbeck, Dr Nathanson, Ms Friebel, and
Dr Domchek are supported by the Basser Research
Center at the University of Pennsylvania. Dr
Nathanson is supported by the Breast Cancer
Research Foundation. Drs Domchek and Nathanson
are supported by the Rooney Family Foundation. Dr
Poppe is supported by R01-CA112520 from NIH.
Cancer Research UK provided financial support for
this work. Dr Antoniou is a Senior Cancer Research
UK Cancer Research Fellow. Dr Phillips is a National
Breast Cancer Foundation (Australia) Practitioner
Fellow.http://jama.jamanetwork.com/journal.aspx2016-04-30hb201