Integrative Genomic Characterization And Crispr-Mediated Gene Editing Studies Identify Iraks As Novel Therapeutic Targets For Inflammation-Driven Prostate Tumorigenesis

A major drawback to accurate diagnosis and treatment of inflammation-driven prostate cancer (PCa) progression is our limited understanding of the molecular mechanisms underlying aberrant inflammation signaling in PCa patients. Since asymptomatic chronic inflammation is hard to diagnose, we do not have adequate knowledge of how specific genes within the inflammatory cascade drive PCa aggressiveness. Hence, an integrative genomic approach may provide us with effective prognostic and diagnostic tools to manage inflammation-driven PCa progression. The aim of this study was to characterize inflammation-associated hub genes as predictors of PCa progression and investigate the effect of aberrant signaling of interleukin-1 receptor-associated kinases (IRAKs) on prostate tumorigenesis. WES and RNA-seq datasets from a total of 726 PCa patients, stratified into subtypes: primary PCa (PPC; n=493), metastatic PCa (MPC; n=150) and the castration-resistant PCa (CRPC; n=52) and neuroendocrine PCa (NEPC; n=30) from 3 cohort studies were acquired from cBioPortal. A bioinformatics pipeline was designed to analyze the datasets. Weighted gene co-expression network analysis (WGCNA) was used to construct gene co-expression networks and identify inflammation hub genes associated with PCa progression. The top inflammation hub genes, such as ILR1, TLRs, IRAK1-4, and NF-kB were validated. IRAK1-4 hub genes were found to be differentially expressed and genetically altered in NEPC and CRPC (\u003e40%) compared to PPC and MPC ( Citation Format: Saheed Oluwasina Oseni, Mirjana Pavlovic, James Hartmann, James Kumi-Diaka. Integrative genomic characterization and CRISPR-mediated gene editing studies identify IRAKs as novel therapeutic targets for inflammation-driven prostate tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 995.