Toward the genetic landscape of prostate cancer in India: insights from whole-exome and low-pass whole-genome sequencing of formalin-fixed paraffin-embedded tumor tissues

Introduction Prostate cancer (PCa) is a leading malignancy in men, with global incidence showing geographical variations. In India, PCa burden is increasing, especially in urban areas and for men over 50 years of age. Our collaborative effort with the Cancer Prostate Consortium of India (CAPCI) aims to map the genetic landscape of PCa in India, investigate somatic mosaicism, and assess the utility of low-pass whole-genome sequencing (LP-WGS) in determining PCa pathogenesis. Materials and methods We performed variant calling using the CONVEX pipeline on whole-exome sequencing (WES) and LP-WGS samples, categorized by tumor grades. Results and discussion ClinVar validation of WES variants identified 12 consensus somatic variants mapped to gnomAD, with 11 being pathogenic, likely pathogenic, or variants of uncertain significance (VUS). We also screened 956 germline variants common to at least two of the 49 samples, identifying 88 common variants, including missense and small InDels. Common and unique somatic variants were found in APC, BRAF, ATM, TP53, SMAD4 and CHEK2 genes. Four of these (rs62619935, rs202160435, rs121913343, and rs141568342) are extremely rare (MAF <= 0.001), seven single nucleotide variants (SNVs) are novel, with four being VUS. Pathogenic somatic variants in higher Gleason score samples (4+4 and 4+3) were homozygous, while benign prostatic hyperplasia (BPH) samples with lower Gleason scores were heterozygous, aligning with population stratification. Whereas the rs1042522 variant in the TP53 gene, with a gnomAD MAF of nearly 38%, was a common somatic SNV, we also identified distinct CAG repeat mosaicism associated with PCa risk.