Multimodal Meta-Analysis of 1,494 Hepatocellular Carcinoma Samples Reveals Significant Impact of Consensus Driver Genes on Phenotypes.

Abstract

Although driver genes in hepatocellular carcinoma (HCC) have been investigated in various previous genetic studies, prevalence of key driver genes among heterogeneous populations is unknown. Moreover, the phenotypic associations of these driver genes are poorly understood. This report aims to reveal the phenotypic impacts of a group of consensus driver genes in HCC. We used MutSigCV and OncodriveFM modules implemented in the IntOGen pipeline to identify consensus driver genes across six HCC cohorts comprising 1,494 samples in total. To access their global impacts, we used The Cancer Genome Atlas (TCGA) mutations and copy-number variations to predict the transcriptomics data, under generalized linear models. We further investigated the associations of the consensus driver genes to patient survival, age, gender, race, and risk factors. We identify 10 consensus driver genes across six HCC cohorts in total. Integrative analysis of driver mutations, copy-number variations, and transcriptomic data reveals that these consensus driver mutations and their copy-number variations are associated with a majority (62.5%) of the mRNA transcriptome but only a small fraction (8.9%) of miRNAs. Genes associated with <i>TP53, CTNNB1</i>, and <i>ARID1A</i> mutations contribute to the tripod of most densely connected pathway clusters. These driver genes are significantly associated with patients' overall survival. Some driver genes are significantly linked to HCC gender (<i>CTNNB1, ALB, TP53</i>, and <i>AXIN1</i>), race (<i>TP53</i> and <i>CDKN2A</i>), and age (<i>RB1</i>) disparities. This study prioritizes a group of consensus drivers in HCC, which collectively show vast impacts on the phenotypes. These driver genes may warrant as valuable therapeutic targets of HCC.