Abstract A019: Identification and Genomic Analysis of miRNA-mRNA Binding Site SNPs in Hepatitis C Virus-Associated Hepatocellular Carcinoma

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Abstract Hepatitis C virus (HCV) infection is a major risk factor for hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths globally. MicroRNAs (miRNAs) play critical roles in gene regulation, and single nucleotide polymorphisms (SNPs) within miRNA binding sites can disrupt this regulation, potentially influencing HCC pathogenesis. The present study aims to identify and characterize SNPs within miRNA binding sites of genes associated with HCV- induced HCC (HCV-HCC). A comprehensive bioinformatics analysis workflow was devised. HCV-specific differentially expressed (DE) miRNAs and mRNAs were extracted from literature and databases. SNPs in the 3' UTRs of HCV-HCC genes were identified, and their impact on miRNA binding was predicted using PoymiRTS and TargetScan. RNAhybrid was used to estimate minimum folding energy (MFE) differences (ΔMFE) between mutant and wild types. Functional enrichment analysis was conducted to elucidate the biological processes affected by these SNPs. Our analysis revealed several significant alterations in miRNA-mRNA binding pairs due to SNPs within genes associated with HCV-HCC. For instance, among the downregulated genes in HCV-HCC, the SNP in CTSB (rs3088245; 193T>C) predicted to increase the stability of the miR-27b - CTSB duplex (ΔMFE: 1.4), suggesting enhanced binding and potentially improved repression of CTSB. Conversely, the SNP in EGR2 (rs61865883; 287 T>A) decreased the stability of the miR-140-5p - EGR2 mRNA interaction (ΔMFE: -1.9), suggesting a weaker binding affinity and potentially reduced repression of EGR2 expression. Considering the tumor suppressor role of EGR2, presence of this SNP is likely to reflect good prognosis. For the upregulated gene oncogene, XIAP, the SNP (rs6648556; 5892 T>C) is predicted to enhance the binding of miR- 200c (ΔMFE: 1.5), likely resulting in increased suppression of XIAP expression in patients carrying this SNP and improved prognosis. Our study emphasizes the importance of considering genetic variations in miRNA binding sites in the context of HCV-HCC. These SNPs may serve as genetic modifiers influencing disease susceptibility and progression. Further experimental studies are warranted to explore their potential as therapeutic agents and predictors of prognosis in HCV-HCC patients. Citation Format: Azeem M Butt, Anum Qamar, Shafiqa Siddique. Identification and Genomic Analysis of miRNA-mRNA Binding Site SNPs in Hepatitis C Virus-Associated Hepatocellular Carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A019.