The landscape of epigenetic alterations in the prostate cancer patient cohort from India

Prostate cancer (PCa) ranks as the third most prevalent malignancy among men in India, where it is frequently diagnosed at its advanced stage due to a lack of routine screening and awareness. PCa is a highly heterogeneous disease, comprising multiple molecular subtypes and exhibiting significant ethnic disparities. Its progression is driven by a cascade of genetic and epigenetic alterations that dysregulate key gene networks and signaling pathways. The global molecular landscape of PCa patients of Indian ethnicity has remained unaddressed. Hence, as a prospective study, we characterized the aberrant DNA methylation pattern in PCa specimens of Indian origin and performed Illumina EPICv2 array-based profiling of fresh, treatment-naïve PCa (N=32), Benign Prostatic Hyperplasia (BPH; N=7) and one high-grade prostatic intraepithelial neoplasia tumor specimens. Using Sesame pipeline, we have identified genome-wide differentially methylated loci in PCa specimens to understand the epigenetic aberrations prevalent in this cohort. We observed significant hypermethylation in the regulatory regions of GSTP1 , APC , RARB, and RASSF1, while TDRD1 , CTBP1, and KLK3 showed hypomethylation. Moreover, key cancer and development-linked processes such as stem cells pluripotency signaling, and synaptic signaling were observed to be dysregulated in PCa specimens compared to BPH. Additionally, hypermethylated regulatory regions exhibited reduced chromatin occupancy of PCa-driving transcription factors such as AR and ERG, while hypomethylated regions showed increased occupancy. Unsupervised hierarchical clustering identified a distinct subset of PCa patients with elevated DNA methylation levels independent of their Gleason grade. Moreover, mapping genetic alterations in matched Indian PCa patients would offer a framework for patient stratification, enabling tailored therapeutic interventions driven by distinct epigenomic and genomic aberrations. In conclusion, our study for the first time, explored the global epigenetic profile of Indian PCa patients while identifying key DNA methylation aberrations and dysregulated pathways driving disease progression that would help improve PCa diagnostics and forward our understanding of PCa pathogenesis.