A Population-Based Analysis of BRCA1/2 Genes and Associated Breast and Ovarian Cancer Risk in Korean Patients: A Multicenter Cohort Study

Abstract

In this study, we performed a comprehensive analysis of BRCA1/2 variants and associated cancer risk in Korean patients considering two aspects: variants of uncertain significance (VUS) and pathogenic or likely pathogenic variants (PLPVs) in BRCA1 and BRCA2. This study included 5433 Korean participants who were tested for BRCA1/2 genes. The BRCA1/2 variants were classified following the standards/guidelines for interpretation of genetic variants and using a multifactorial probability-based approach. In Korea, 15.8% of participants had BRCA1 or BRCA2 PLPVs. To estimate the additional sample numbers needed to resolve unclassified status, we applied a simulation analysis. The simulation study for VUS showed that the smaller the number of samples, the more the posterior probability was affected by the prior probability; in addition, more samples for BRCA2 VUS than those of BRCA1 VUS were required to resolve the unclassified status, and the presence of clinical information associated with their VUS was an important factor. The cumulative lifetime breast cancer risk was 59.1% (95% CI: 44.1–73.6%) for BRCA1 and 58.3% (95% CI: 43.2–73.0%) for BRCA2 carriers. The cumulative lifetime ovarian cancer risk was estimated to be 36.9% (95% CI: 23.4–53.9%) for BRCA1 and 14.9% (95% CI: 7.4–28.5%) for BRCA2 carriers.

Basic knowledge for counseling patients undergoing risk-reducing salpingo-oophorectomy

“…Women with germline BRCA1/2 mutations have a substantially increased lifetime risk for developing certain cancers, including breast, epithelial ovarian, fallopian tube, peritoneal, pancreatic, and prostate cancer [ 12 , 27 ]. They have a 10% to 65% cumulative lifetime risk of EOC (39-65% for women with a BRCA1 and 11-23% for women with a BRCA2) compared to women in the general population who have a lifetime risk of 1-2% [ 12 , 28 , 29 ].…”

“…They have a 10 to 65% cumulative lifetime risk of EOC (39-65% for women with a BRCA1 and 11-23% for women with a BRCA2) compared to women in the general population who have a lifetime risk of 1-2% [11,27,28].…”

Discovery of BRCA1/BRCA2 founder variants by haplotype analysis

“…We divided these recurrent variants into groups A to C, as described above. Two BRCA2 gene variants were strati ed into group A, c.7480C>T 22,40 and c.3744_3747del [41][42][43] . There were two variants, c.10150C>T [44][45][46] and c.5576_5579del [47][48][49] , in group B and three variants, c.1399A>T 39,50,51 , c.3018del 52 , and c.6724_6725del 53,54 in group C (Table 3).…”

BRCA1-specific machine learning model predicts variant pathogenicity with high accuracy

“…Deleterious BRCA1 mutations are transmitted in an autosomal dominant pattern with cumulative cancer risk estimates for a 70-yr-old woman being between 40% and 87% for breast cancer and 16% to 68% for ovarian cancer ( 5 – 15 ). The likelihood of carrying an inherited mutation in BRCA varies across populations with an estimated prevalence in the general population between 0.2% and 0.8%; ∼1 in 400 to 139 individuals ( 16 – 19 ).…”