Exploration of BRCA1 and BRCA2 mutations in gastric cancer patients through next generation sequencing: implications for diagnosis and therapy

Objectives: The study aims to characterize BRCA1/2 mutations in Pakistani gastric cancer (GC) patients, identifying unique pathogenic variants and evaluating their potential as diagnostic biomarkers, while also exploring therapeutic avenues for personalized treatment strategies.

Methodology: In this study, we investigated the role of Breast Cancer gene 1 (BRCA1) and Breast Cancer gene 2 (BRCA2) mutations in Pakistani GC patients and their functional implications using Next-Generation Sequencing (NGS).

Results: Through NGS, we identified a total of 19 mutations in BRCA1 and 11 mutations in BRCA2, all with high mutation quality scores. In silico analysis revealed one pathogenic mutation in BRCA1 and one in BRCA2, indicating a potential link to disease development. Notably, two pathogenic mutations (BRCA1 p.Ala1823Ser and BRCA2 p.Gln92fs) were exclusively observed in the Pakistani GC population, suggesting unique genetic markers. Further examination utilizing The Cancer Genome Atlas (TCGA) data confirmed the absence of these mutations in non-Pakistani GC samples, emphasizing their specificity. Sanger sequencing validated these findings. Real Time Quantitative PCR (RT-qPCR) analysis indicated significantly decreased BRCA1/2 gene expression in samples harboring pathogenic mutations, suggesting their potential as biomarkers for GC diagnosis. Immunohistochemistry corroborated this by showing reduced protein expression levels in mutated samples. Enrichment analysis highlighted associations of BRCA1/2 genes with DNA damage response pathways and cancer-related processes. DrugBank exploration revealed potential therapeutic agents targeting mutated BRCA1/2, such as Cisplatin and Estradiol, offering new avenues for treatment.

Conclusion: Our study identifies novel BRCA1/2 mutations specific to Pakistani GC patients, suggesting a distinct genetic susceptibility profile. These findings not only contribute to understanding GC pathogenesis but also hold implications for personalized treatment strategies in this population.