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.
Highlights
BRCA1 and BRCA2 play essential roles in maintaining genome stability by repairing double-strand DNA damage through homologous recombination (Roy et al, 2011)
40.9% of BRCA variants in the cancer cohort were pathogenic variants, which was much higher than the value of 3.3% in general population (p < 0.000); VUS and likely benign were significantly higher in general population than those in the cancer cohort (24.9% vs. 14% and 39.7% vs. 17%, p < 0.009, 0.000 ) (Table 1)
It is well known that the number of benign variants is higher in the general population than in the cancer cohort, and the number of pathogenic mutations is higher in the cancer cohort than in the general population
Summary
BRCA1 and BRCA2 (hereafter refer as BRCA) play essential roles in maintaining genome stability by repairing double-strand DNA damage through homologous recombination (Roy et al, 2011). While the majority of variants can be beneficial or neutral, those occurred at specific positions can damage the Taiwanese BRCA1 and BRCA2 Variation function of BRCA, causing genome instability and increased risk of breast cancer, ovarian cancer, and other types of cancer (Kuchenbaecker et al, 2017). As BRCA variation is mostly of the germline nature, the later life stage of cancer occurrence provides a unique opportunity to prevent BRCA variation–caused cancer by early identification of the pathogenic variant carriers before cancer development (Burke et al, 1997). We analyzed BRCA variation in Asian populations such as Indian, Chinese, Korean, and Japanese, and revealed that ethnic-specific BRCA variation is widely present in these Asian populations (Bhaskaran et al, 2020). The Taiwanese population provides a unique model to study BRCA evolution and its impact on human health
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
