Understanding the genetic epidemiology of hereditary breast cancer in India using whole genome data from 1029 healthy individuals

Abstract

Aim: Breast cancer is the most highly reported cancer in India as well as globally (Globocan 2020). Genetic testing could help tackle the increasing cancer burden by enabling carriers of pathogenic variants obtain an early diagnosis through increased surveillance, and help guide treatment, and in some cases enable prevention. However, accurate interpretation of variant pathogenicity must be established in a population-specific manner to ensure effective use of genetic testing. Further, since BRCA1 and BRCA2 are importance breast cancer genes, even rare variants must be studied for their potential effect on the disease. Materials and Methods: We query the IndiGen data obtained from whole genome sequencing of 1029 Indian individuals, and perform variant classification of all reported BRCA variants according to the gold-standard ACMG/AMP guidelines to establish disease epidemiology. We further implement machine learning approaches to classify all reported non-benign variants, and create a ready-reference of variants classified in a manner close to ACMG guidelines at scale. Results: We determined the genetic prevalence to be the following: 1 in nearly 341 individuals for BRCA1, and 1 in nearly 170 individuals for BRCA2 are likely to be carriers of pathogenic mutations. Overall, 1 in nearly 114 individuals are likely to be carriers of pathogenic BRCA mutations. Further, using the brca-NOVUS tool, we classified 1,54,045 genetic variants across 18 population sets and 4 large variant repositories as either pathogenic or benign. Conclusion: The high population prevalence indicates a greater need of studying genetic variants linked with breast cancer in an Indian population specific manner. To the best of our knowledge, this is the first and most comprehensive population-scale genetic epidemiological study of BRCA-linked breast cancer variants reported from India.