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

Abstract

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.

Figure 1. Analysis Workflow

Analyses undertaken are listed in the order in which they are presented in the text. ^aThe functional domains were the RING, coiled coil, BRCT, BRC, DNA binding, oligonucleotide-binding folds, and tower domains.

Figure 2. Hazard Ratio of Breast Cancer Relative to the Hazard Ratio of Ovarian Cancer by BRCA1 Nucleotide Position

The graph shows the ratio of hazard ratios (blue data markers) and 95% CI (error bars) for the mutation bins defined across the span of the coding DNA sequence of the BRCA1 gene. Black arrowheads under the bins indicate 2 founder mutations of clinical interest in the Ashkenazi Jewish population. Regions inferred to be breast cancer cluster regions (BCCRs) and ovarian cancer cluster regions (OCCRs) are shown at the bottom. Solid light blue lines indicate regions found to be statistically significant; dashed light blue lines indicate regions in the same direction of effect that were not statistically significant. eTable 2 in the Supplement lists the bins and risks used to define the BCCRs and OCCRs.

Figure 3. Hazard Ratio of Breast Cancer Relative to the Hazard Ratio of Ovarian Cancer by BRCA2 Nucleotide Position

The graph shows the ratio of hazard ratios (blue data markers) and 95% CI (error bars) for the mutation bins defined across the span of the coding DNA sequence of the BRCA2 gene. The black arrowhead under the bins indicates a founder mutation of clinical interest in the Ashkenazi Jewish population. The regions inferred to be breast cancer cluster regions (BCCRs) and ovarian cancer cluster regions (OCCRs) are shown at the bottom; the solid light blue lines indicate regions found to be statistically significant. eTable 3 in the Supplement lists the bins and risks used to define to define the BCCRs and OCCRs.