Abstract 5351: The landscape of somatic mutations and copy-number alterations in the Indian Cohort of Prostate Cancer Patients

Abstract In India, prostate cancer (PCa) has the third highest incidence rate among males and is often diagnosed at the advanced stage. PCa is known to be molecularly heterogeneous, and an in-depth characterization of its subtypes by geographical ethnicities may aid in the understanding of its etiology and disparities. Hence, we perform molecular characterization of PCa patients from India. Integrative genomics studies categorized PCa into molecular subtypes based on genetic aberrations (e.g., somatic mutations, INDEL, etc.). Although genetic factors are known to impact PCa pathobiology, genomic profiling of Indian PCa patients and its clinical utility remain largely unexplored. Thus, in a prospective study, we performed whole exome sequencing (WES) of treatment-naive primary PCa (N=90) and benign prostatic hyperplasia specimens (N=14) along with matched blood. Our findings reveal distinct genetic alterations unique to the Indian cohort, wherein an elevated somatic tumor mutational burden and an increased percentage of clinically actionable alterations were noted. About 80% of the somatic variants (called using Mutect2) were found to be missense mutations with a high recurrence of C>T transitions, a signature of age-related human malignancies. Several novel pathogenic alterations affecting critical domains of the cancer-associated genes (e.g., APC, BRCA2, PI3KCA, etc.) were found, which have not been reported in the dbSNP or COSMIC databases. Systematic comparison of our findings with primary PCa data available at The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) revealed distinct genomic alterations in Indian PCa patients: specifically, 35% of the patients showed presumed actionable lesions in the RTK-Ras pathway genes, while 10% had mutations in the PI3K pathway genes, and 21% of all the specimens harbored putative inactivating mutations of genes involved in the homologous recombination repair pathway. We also found major differences in the mutational frequency of some driver genes, such as ATRX, PIK3C2G, TAL1, etc., compared to the TCGA-PRAD cohort. Furthermore, GISTIC2 analysis revealed significant arm-level amplification at 8q (MYC, GLI4), 7q (GNB2, PDIA4), and 16p (TELO2, TSC2) regions and deletion at 8p (NKX3.1, MSR1), 9p (CDKN2A, CDKN2B), and 13q (RB1, BRCA2) regions. We also identified recurrent focal amplifications at 9q, 14q, and 11q, and deletions at 16q, 10q, and 5q loci. Further, integrating WES data with transcriptome data would be helpful in categorizing PCa patients based on gene fusion status and prioritizing functionally impactful and actionable variants. Collectively, our findings reveal molecular heterogeneity among PCa patients from India, leading to the identification of clinically relevant candidates that need to be further validated and would help in strategizing therapies and clinical management of this disease. Citation Format: Tanay Biswas, Pankaj Vats, Vipul Bhatia, Atin Singhai, Alok Srivastava, Abhishek Chauhan, Manzoor Ahmad, Piyush Tripathi, Sanjeev Mehrotra, Anjali Tewari, Nuzhat Husain, Apul Goel, Nallasivam Palanisamy, Bushra Ateeq. The landscape of somatic mutations and copy-number alterations in the Indian Cohort of Prostate Cancer Patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5351.