Abstract A004: The landscape of genomic and transcriptomic signatures in Indian prostate cancer patients

Abstract Prostate cancer (PCa) is the second most common cancer worldwide and sixth in India where it is often detected at advanced stages. It is a genetically heterogeneous malignancy classified into distinct subtypes, characterized by ETS gene fusions, elevated SPINK1 expression, and recurrent mutations in SPOP, FOXA1 etc. Although genetic factors are known to impact PCa pathobiology, genomic profiling of Indian PCa patients and its clinical utility remain largely unexplored. Hence, we performed whole-exome sequencing on fresh needle core prostate biopsies along with matched blood obtained from 104 Indian patients. The cohort comprises treatment-naïve primary PCa (n=89), benign prostatic hyperplasia (BPH; n=13), and two prostatic intraepithelial neoplasia samples. Our analysis reveals distinct genetic features in the Indian cohort, marked by an elevated somatic tumor mutational burden and a higher percentage of clinically actionable alterations. Several unique somatic drivers and novel pathogenic mutations in well-known cancer-associated genes (APC, BRCA2, PIK3CA, etc.) were identified in this cohort. Additionally, analysis of 104 specimens revealed germline variants in BRCA1, BRCA2, ATM, NTHL1, and many other cancer-related genes. Furthermore, GISTIC2 analysis identified amplifications at 8q (MYC, GLI4) and 11q (CCND1, FGF3), and deletions at 8p (NKX3.1, MSR1) and 13q (RB1, BRCA2) regions. A systematic comparison with the TCGA-PRAD cohort revealed both convergent and divergent alterations features. Notably, 71% of tumors exhibited aberrations in DNA damage repair pathways, 58% in RTK-RAS, and 52% in PI3K signaling, with 90% harboring at least one potentially actionable alteration. Further, whole transcriptome sequencing on fresh PCa biopsies (n=53) and BPH (n=10) specimens was performed, identifying 1,358 differentially expressed genes. Of these, the homeobox transcription factor DLX1 emerged as the most significantly upregulated gene along with elevated expression of other androgen signaling-associated genes (e.g., PSGR, CCAT2) and metabolic reprogramming markers (MMP1, ALOX15). Contrariwise, several tumor-suppressive and immune-modulatory genes, such as FHIT, CD48, and IL21 were downregulated. Functional enrichment revealed enhanced androgen response and lipid metabolism signatures, along with suppression of apoptosis and inflammatory pathways which delineate an immunologically “cold” yet metabolically reprogrammed transcriptome. Moreover, a recurrent ETS gene fusion was observed, predominantly involving ERG (41.8%) and a notable subset with ETV6 (9.1%), ETV4 (5.5%), and ETV1 (9.1%) alongside clinically actionable gene fusions involving BRAF, RAF1, PIK3CA/B, and RSPO2 (∼10% cases). Collectively, our findings reveal molecular heterogeneity among PCa patients from India and offer a critical foundation for improved risk stratification, early diagnosis and 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 genomic and transcriptomic signatures in Indian prostate cancer patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A004.