Multi-Omics SMR and Experimental supportive analyses Decipher Causal Drivers Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a highly prevalent and fatal digestive system malignancy, challenging to treat due to its latent onset and non-specific symptoms in advanced stages. Somatic mutations play a crucial role in hepatocarcinogenesis, with nearly half of HCC patients carrying oncogenic driver mutations such as TP53, CTNNB1, or TERT. In parallel, germline susceptibility variants identified by genome-wide association studies (GWAS) — including loci near TERT, MBOAT7, TM6SF2, and PNPLA3 — reveal inherited predisposition that shapes the molecular landscape for HCC development. Despite recent therapeutic advancements, long-term survival remains suboptimal, necessitating a deeper understanding of its pathogenesis and the identification of precise molecular targets. Traditional genomic studies, such as genome-wide association studies (GWAS), have successfully identified associated variants; however, due to their statistical design, they do not provide direct causal inference, functional supportive analyses, or comprehensive insight into multi-level molecular regulation and tumor microenvironment heterogeneity, serving instead as a critical starting point for subsequent functional and integrative analyses.