Overview and Clinical Significance of Multiple Mutations in Individual Genes in Hepatocellular Carcinoma

Abstract

BackgroundMultiple mutations (MMs) within individual oncogenes have been newly characterized as a mechanism for promotion of carcinogenesis. We investigated the spectra of the MMs and the clinical significance in hepatocellular carcinoma (HCC). MethodsWhole-exome sequencing and gene expression profiling were performed in 223 surgically resected HCCs. ResultsMMs within individual genes was identified in 178 samples (79.8%, MMs tumors). All the remaining samples carried single mutation (20.2%, SM tumors). Mutations identified as MMs show different mutational patterns with higher functional impact compared with mutations identified as SM. Recurrence-free survival was significantly worse in the group with MMs tumors than the group with SM tumors (P = 0.012). MMs tumor was identified as an independent predictor for worse prognosis (hazard ratio, 1.72; 95%, P = 0.045). MMs were observed particularly in MUC16 (15% of samples with at least one mutation in the gene) and CTNNB1 (14%). Although there was no significant difference in MUC16 mRNA expression between MUC16 wild-type and MUC16 SM tumors, the expression in MUC16 MMs tumors was significantly enhanced compared with MUC16 SM tumors (P < 0.001). MMs in MUC16 were associated with viral hepatitis, higher tumor markers and vascular invasion. Recurrence-free survival was significantly worse in the MUC16 MMs group than the MUC16 SM group (P = 0.022); no significant difference was observed between the MUC16 SM group and MUC16 wild-type group (P = 0.324).ConclusionsMMs are relatively common driver events that selectively occur in specific oncogenes and function in tumor-promoting activity.