Potential excess mortality in BRCA1/2 mutation carriers beyond breast, ovarian, prostate, and pancreatic cancers, and melanoma

Abstract

Background: Although the increase in risk of developing breast, ovarian, and prostate cancer in BRCA1 and BRCA2 mutation carriers has been studied extensively, its impact on mortality is not well quantified. Further, possible effect of BRCA mutations on non-cancer mortality risk has not been examined.

Methodology/principal findings: Using mortality data from the relatives of 5,287 genotyped participants, of whom 120 carried a BRCA Ashkenazi Jewish founder mutation, in a community-based study of the Ashkenazi Jewish population in the Washington D.C area, we examined the association between the three Ashkenazi BRCA founder mutations and risk of overall and non-cancer mortality. To examine risks beyond the established effects of these mutations, we analyzed the data excluding both deaths and follow-up times after reported diagnosis of melanoma and cancer of the breast, ovary, prostate, and pancreas. Using an extension of the kin-cohort method that accounts for informative censoring, we estimated that, in the absence of breast, ovarian, and pancreatic cancers, and melanoma, female carriers had a life expectancy that was 6.8 years lower (95% CI: 1.2-10.5) than non-carriers. In male mutation carriers, the reduction in life expectancy, in the absence of prostate and pancreatic cancers and melanoma, was 3.7 (95% CI: -0.4, 6.8) years. When deaths and follow-up times after any cancer diagnosis were excluded, the difference in life expectancy was 5.7 years for women (95% CI: -0.1, 10.4) and 3.7 years for men (95% CI: -0.4, 6.9). An overall test of association for men and women together showed a statistically significant association between BRCA1/2 mutations and increased non-cancer mortality (p = 0.024).

Conclusions/significance: These findings suggest that there may be unknown effects of BRCA1/2 mutations on non-neoplastic diseases that cause death at older ages.

Figure 1. Cumulative incidence of all-cause mortality.

Panel 1 shows the cumulative incidence of all-cause mortality among female first-degree relatives of participants in the Washington Ashkenazi Study. Panel 2 shows the corresponding kin-cohort estimate of cumulative mortality risk among female carriers and non-carriers of BRCA1/2 Ashkenazi Jewish founder mutations.

Figure 2. Cumulative incidence of mortality risk in the absence of established BRCA mutation-associated cancers.

Estimated cumulative risk of mortality among females in the absence of breast, ovarian, pancreatic cancer, and melanoma is shown in panel A. Panel B shows the estimated cumulative risk of mortality among males in the absence of melanoma, prostate, and pancreatic cancer.

Figure 3. Estimated cumulative risk of mortality in the absence of any cancer.

The figure shows the estimated cumulative risk of mortality in the absence of any cancer among females (panel A) and males (panel B).