Exon-Specific Targeted Analysis of BRCA1 and BRCA2 Mutations in Bangladeshi Breast Cancer Patients

Breast cancer (BC) is a leading cause of death among women. Pathogenic variations (PVs) in BRCA1 and BRCA2 genes increase the risk of hereditary and Triple-negative breast cancer (TNBC). Despite its great importance, NGS-based genetic testing of BRCA1 and BRCA2 in Bangladesh is out of reach of most patients because of its high cost.

To overcome this challenge, this study explored whole genome databases (cBioPortal, gnomAD, dbSNP) to investigate whether sequencing selected exons in BRCA1 and BRCA2 genes may provide meaningful clinical interpretation of BC risk.

Exons 4 and 16 of BRCA1 and exons 18, 23 and 25 of BRCA2 were selected for targeted analysis. According to the aforementioned databases, 10 and 21 mutations are pathogenic in the targeted regions of BRCA1 and BRCA2 respectively. To evaluate the presence or absence of these germline pathogenic variations (PV) in Bangladeshi BC patients, we collected blood samples from 13 subjects, among whom, 9 were diagnosed with BC, and 4 without cancerous tumors but with family history and breast lump.

Analysis of 13 patient samples revealed no PVs in the targeted regions. Within the BRCA1 gene, 5 of the 10 sites, and within the BRCA2 gene, 10 of the 21 sites associated with pathogenic variations were successfully sequenced and clearly interpretable. However, comparison with the reference sequence confirmed the absence of PVs in the targeted regions of both BRCA1 and BRCA2. In silico analysis indicated that missense mutations are the predominant type of variation in both genes.

This study, although limited by sample size, demonstrates that even exons enriched for pathogenic mutations may not be sufficiently representative for detecting PVs through targeted sequencing of BRCA1 and BRCA2. Comprehensive sequencing of the full lengths of BRCA1 and BRCA2 may be necessary to ensure confident clinical interpretation in BC patients.