BRCA1 and BRCA2 Variation in Taiwanese General Population and the Cancer Cohort

Abstract

BRCA1 and BRCA2 (BRCA) play essential roles in maintaining genome stability. Rapidly evolving human BRCA generates oncogenic variants causing high cancer risk. BRCA variation is ethnic-specific in reflecting adaptation and/or effects of genetic drift. Taiwanese population of 23.8 million is an admixture of multiple ethnic origins; Taiwan’s subtropical and tropical climate and geographically islandic location provide a unique natural environment. Therefore, Taiwanese population provides a unique model to study human BRCA variation. Through collecting, standardizing, annotating, and classifying publicly available BRCA variants derived from Taiwanese general population and the cancer cohort, we identified 335 BRCA variants, of which 164 were from 1,517 non-cancer individuals, 126 from 2,665 cancer individuals, and 45 from both types of individuals. We compared the variant data with those from other ethnic populations such as mainland Chinese, Macau Chinese, Japanese, Korean, Indian, and non-Asians. We observed that the sharing rates with other Asian ethnic populations were correlated with its genetic relationship. Over 60% of the 335 Taiwanese BRCA variants were VUS, unclassified variants, or novel variants, reflecting the ethnic-specific features of Taiwanese BRCA variation. While it remains challenging to classify these variants, our structural and in silico analyses predicted their enrichment of BRCA deleterious variants. We further determined the 3.8% prevalence of BRCA pathogenic variants in the Taiwanese breast cancer cohort, and determined 0.53% prevalence of the BRCA pathogenic variants in Taiwanese general population, with the estimated 126,140 BRCA pathogenic variant carriers. We identified BRCA2 c.5164_5165delAG at BRCA2 BRC6 motif as a potential founder mutation in Taiwanese population. Our study on BRCA variation in Taiwanese and other East Asian populations demonstrates that ethnic specificity is a common phenomenon for BRCA variation in East Asian population; the data generated from the study provide a reference for clinical applications in BRCA-related cancer in Taiwanese population.

Diagnostic rate of germline pathogenic variants in pancreatic ductal adenocarcinoma patients using whole genome sequencing

“…The BRCA2 variant was consistently reported to be pathogenic; for the SPINK1 variant, there were conflicting interpretations of pathogenicity, with nine identifying it as pathogenic and one as uncertain significance. These two variants had both been reported as pathogenic variants in published pancreatic cancer studies ( Chian et al, 2021 ; Yin et al, 2022 ). Although the other variants in BRCA1 , ATM , and POLQ were not previously reported and were identified as novel variants in this current study, pathogenic variants in these genes have also been reported in pancreatic cancer and therefore these genes have been known to cause PDAC ( Earl et al, 2020 ; Mizukami et al, 2020 ).…”

Human BRCA pathogenic variants were originated during recent human history

“…The prevalence of BRCA PLP is between 0.2% and 0.5% in modern human population. For example, the prevalence is 0.26% in Japanese population (Momozawa et al, 2018), 0.29% in Macau population (Qin et al, 2021), 0.38% in Chinese population (Dong et al, 2021), 0.38% in Mexican population (Fernandez-Lopez et al, 2019), 0.39% in Malaysian population (Wen et al, 2018), 0.53% in Taiwanese population (Chian et al, 2021), and 0.53% in Caucasian populations Positive selection imposed on the reproductive stage can select the BRCA PLP not deleterious at the stage. However, our current study does not determine whether one or both of the explanations could contribute to the higher prevalence of BRCA PLP in modern human population.…”

Pathogenicity Reclassification of Genetic Variants Related to Early-Onset Breast Cancer among Women of Mongoloid Origin

“…Our data are consistent with other studies in the field of VUS reclassification of BRCA1/2 genes. The problem regarding VUS reclassification has been discussed mostly for Asian populations, where the frequency of VUS reaches 60% (Nakamura et al, 2016;Kwong et al, 2016;Chian et al, 2021). In the study of Sinha (2020), the authors created own model where they measured the effect of variants on the structural conformations of BRCT repeats using molecular dynamics simulation (MDS) consisting of RMSD (Root-mean-square-deviation), RMSF (Root-mean-square-fluctuations), Rg (Radius of gyration), SASA (Solvent accessible surface area), NH bond (hydrogen bond) and Covariance analysis.…”