Prevalence and spectrum of homologous recombination repair mutations in patients with metastatic prostate cancer from India

BACKGROUND: Alterations in genes involved in homologous recombination repair (HRR) occur in approximately 20%-25% of patients with metastatic prostate cancer and are associated with aggressive biology, poor outcomes, and potential sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). However, frequency and variations in somatic HRR mutations in the Indian population are unknown. METHODS: We analyzed somatic HRR alterations in patients at the All India Institute of Medical Sciences, New Delhi, between 2022 and November 2024. Targeted next-generation sequencing of 15 HRR genes was performed on tumor tissue samples. Demographic and clinicopathological variables were retrieved from medical records, and their associations were assessed. RESULTS: Of 247 patients tested, 167 were evaluable (32.3% tissue failure due to poor DNA yield). Sixty-eight pathogenic HRR alterations were detected across 51 patients (30.5%). ATM was the most frequently altered gene (13.2%), followed by BRCA1 (5.3%), BRCA2 (4.2%), and CDK12 (4.2%). Variants of unknown significance (VUS) were detected in 12% (20) of patients. Patients with HRR alterations had higher baseline PSA values compared with the non-HRR cohort (median 150 vs 100 ng/mL, P = .012). No significant associations were observed with age, Gleason score, disease volume or risk category, or visceral metastases. CONCLUSIONS: This study provides the first comprehensive dataset on the spectrum of somatic HRR mutations in Indian patients with prostate cancer. The prevalence (30.5%) was somewhat higher than the global studies, ATM was the most frequently mutated gene, followed by BRCA1, in contrast to Western and Asian cohorts, where BRCA2 predominates. These findings suggest potential population-specific variations and underscore the need for broader HRR testing to better delineate the genomic landscape of prostate cancer in Indian patients.