Elucidation of the Genomic-Epigenomic Interaction Landscape of Aggressive Prostate Cancer. – UroToday

Majority of prostate cancer (PCa) deaths are attributed to localized high-grade aggressive tumours which progress rapidly to metastatic disease. A critical unmet need in clinical management of PCa is discovery and characterization of the molecular drivers of aggressive tumours. The development and progression of aggressive PCa involve genetic and epigenetic alterations occurring in the germline, somatic (tumour), and epigenomes. To date, interactions between genes containing germline, somatic, and epigenetic mutations in aggressive PCa have not been characterized. The objective of this investigation was to elucidate the genomic-epigenomic interaction landscape in aggressive PCa to identify potential drivers aggressive PCa and the pathways they control. We hypothesized that aggressive PCa originates from a complex interplay between genomic (both germline and somatic mutations) and epigenomic alterations. We further hypothesized that these complex arrays of interacting genomic and epigenomic factors affect gene expression, molecular networks, and signaling pathways which in turn drive aggressive PCa.

We addressed these hypotheses by performing integrative data analysis combining information on germline mutations from genome-wide association studies with somatic and epigenetic mutations from The Cancer Genome Atlas using gene expression as the intermediate phenotype.

The investigation revealed signatures of genes containing germline, somatic, and epigenetic mutations associated with aggressive PCa. Aberrant DNA methylation had effect on gene expression. In addition, the investigation revealed molecular networks and signalling pathways enriched for germline, somatic, and epigenetic mutations including the STAT3, PTEN, PCa, ATM, AR, and P53 signalling pathways implicated in aggressive PCa.

The study demonstrated that integrative analysis combining diverse omics data is a powerful approach for the discovery of potential clinically actionable biomarkers, therapeutic targets, and elucidation of oncogenic interactions between genomic and epigenomic alterations in aggressive PCa.

BioMed research international. 2021 Jan 13*** epublish ***

Tarun Karthik Kumar Mamidi, Jiande Wu, Chindo Hicks

Center for Computational Genomics and Data Science, Departments of Pediatrics and Pathology, University of Alabama-Birmingham School of Medicine, Birmingham, Alabama 35233, USA., Department of Genetics and the Bioinformatics and Genomics Program, Louisiana State University Health Sciences Center, School of Medicine, 533 Bolivar Street, New Orleans, LA 70112-1393, USA.

PubMed http://www.ncbi.nlm.nih.gov/pubmed/33511206

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Elucidation of the Genomic-Epigenomic Interaction Landscape of Aggressive Prostate Cancer. - UroToday