Characterization of BRCA1 and BRCA2 mutations in a large United States sample

Abstract

Purpose: An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families.

Methods: We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family.

Results: In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling.

Conclusion: The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.

Fig 1

Future risks of developing cancer for a female carrier at a range of ages in the next 10-year interval, 20-year interval, and so on. (A) Breast cancer, BRCA1 carrier; (B) breast cancer, BRCA2 carrier; (C) ovarian cancer, BRCA1 carrier; and (D) ovarian cancer, BRCA2 carrier. For example, in the upper left panel, the left-most curve gives the risk of developing breast cancer for a 20-year-old BRCA1 mutation carrier in the next 10 to 50 years. The vertical bars are 95% CIs.

Fig 2

Mean relative risks for US carriers to noncarriers with 95% CIs. The noncarrier incidences are from the Surveillance, Epidemiology and End Results age-conditional probabilities of developing cancer. (A) Breast cancer, BRCA1 carrier; (B) breast cancer, BRCA2 carrier; (C) ovarian cancer, BRCA1 carrier; and (D) ovarian cancer, BRCA2 carrier.