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.
ABSTRACT
BACKGROUND: Germline mutation in BRCA1 and BRCA2 (BRCA) is genetic predisposition for breast and ovarian cancer. Identification of mutation carriers is a critical step to prevent and treat the cancer in the mutation carriers. Human BRCA variation has been well determined as ethnic-specific by studies in Ashkenazi Jewish, Polish and Icelandic populations in the 1990s. However, sufficient evidence is lacking to determine if ethnic-specific BRCA variation is also present in Asia population, which is the largest and the most diversified in modern humans. Our current study aims to investigate ethnic-specific BRCA variation in Asian population. METHODS: We performed a comprehensive data mining to collect BRCA variation data in Indian, Chinese, Korean and Japanese populations derived from over 78 000 cancer and 40 000 non-cancer cases. We standardised all BRCA variation data following the international standard. We made a systematic comparison between the datasets including variant composition, variation spectrum, variant type, clinical class, founder mutation and high-frequent variants. RESULTS: Our analysis showed that over half of the Asian BRCA variants were Asian-specific, and significant differences were present between the four Asia populations in each category analysed. CONCLUSION: Data from our study reveal that ethnic-specific BRCA variation is commonly present in Asia population as existing in non-Asian populations. Our study indicates that ethnicity should be an important factor to consider in prevention and treatment of BRCA mutation-related cancer in the Asia population. We recommend that the current BRCA variation databases should include ethnic variation information in order to function as true global BRCA references.
