Abstract 1693: Mitochondrial-associated DNAJA3 variant and its role in NASH-driven hepatocellular carcinoma

Abstract

Abstract Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a major risk factor for hepatocellular carcinoma (HCC). Despite the known progression from NAFLD to nonalcoholic steatohepatitis (NASH) and eventually HCC, the genetic underpinnings driving this transition remain underexplored. A comprehensive genomics assessment was conducted, encompassing a genome-wide study of variants linked to body fat distribution in 344,369 individuals. Correlating these, significant variants associated with NASH and HCC were discerned in a cohort of 1,009 participants from the NCI-UMD study. Candidate variants underwent further eQTL analysis. Our investigation unveiled the rs3747579-TT variant emerged as significantly associated with NASH-related HCC, serving as an eQTL for mitochondrial DNAJA3. HCC patients harboring this variant presented with diminished DNAJA3 expression, correlating with an unfavorable prognosis. Exploration into the 3D genome architecture has identified potential chromatin topology sites that may influence the regulation of DNAJA3 by rs3747579. Specifically, enhancer loops exhibit allele-specific interactions with rs3747579 in the regulation of DNAJA3. Notably, the rs3747579-CC variant was found to interact with RBFOX2. Beyond its known RNA splicing functions, RBFOX2 might have implications in the chromatin landscape, influencing chromatin dynamics and gene transcription. RBFOX2 knockdown experiments showcased significantly reduced DNAJA3 expression, and luciferase assays highlighted increased activity for the rs3747579-CC allele versus its TT counterpart. In summary, our findings spotlight the rs3747579-TT variant as a potential oncogenic factor in DNAJA3, elucidating its role in the genesis of NASH and progression to HCC. This understanding could pave the way for novel therapeutic interventions in HCC stemming from NAFLD/NASH. Citation Format: Yuto Shiode, Ching-Wen Chang, Xin Wei Wang. Mitochondrial-associated DNAJA3 variant and its role in NASH-driven hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1693.