Characterization of<i>BRCA1</i>and<i>BRCA2</i>Mutations in a Large United States Sample

TLDR

Accurate evaluation of BRCA1/2 penetrance is essential for identifying high‑risk families, yet prior studies have mainly focused on Ashkenazi Jews or non‑US populations. The study aims to estimate BRCA1/2 penetrance in the United States using the largest US‑based cohort of Ashkenazi and non‑Ashkenazi families. The authors assembled 1,948 families (676 Ashkenazi and 1,272 non‑Ashkenazi) through the Cancer Genetics Network, applied a retrospective likelihood method to adjust for oversampling of positive histories, and leveraged detailed pedigrees and Mendelian inheritance to estimate cumulative and prospective cancer risks. The estimated cumulative breast cancer risk at age 70 was 46% for BRCA1 and 43% for BRCA2 carriers, with ovarian cancer risks of 39% and 22% respectively, and relative breast cancer risk declines.

Abstract

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.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.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.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.