DNA Damage Repair Classifier Defines Distinct Groups in Hepatocellular Carcinoma

SIMPLE SUMMARY: DNA repair pathways have been implicated in hepatocellular carcinoma outcomes. We found that hepatocellular carcinomas (HCC) could be separated into two groups (high and low) based on the overall expression of genes involved in DNA repair. Among the low repair group, there were three subgroups, one of which shared features of the high repair group. Given the important role of liver in metabolism and detoxification and its regenerative capacity, proliferation and DNA damage responses are critical in subdividing major biological categories of liver tumors. High repair samples showed more proliferative and regenerative signatures and had poorer outcomes versus the low repair that were more associated with the genes involved in normal liver biology. These biological groups suggest that dysregulation in endogenous liver processes promotes a pro-tumorigenic microenvironment that may facilitate tumor progression or identify tumors that require more substantial clinical intervention. ABSTRACT: DNA repair pathways have been associated with variability in hepatocellular carcinoma (HCC) clinical outcomes, but the mechanism through which DNA repair varies as a function of liver regeneration and other HCC characteristics is poorly understood. We curated a panel of 199 genes representing 15 DNA repair pathways to identify DNA repair expression classes and evaluate their associations with liver features and clinicopathologic variables in The Cancer Genome Atlas (TCGA) HCC study. We identified two groups in HCC, defined by low or high expression across all DNA repair pathways. The low-repair group had lower grade and retained the expression of classical liver markers, whereas the high-repair group had more clinically aggressive features, increased p53 mutant-like gene expression, and high liver regenerative gene expression. These pronounced features overshadowed the variation in the low-repair subset, but when considered separately, the low-repair samples included three subgroups: L1, L2, and L3. L3 had high DNA repair expression with worse progression-free (HR 1.24, 95% CI 0.81–1.91) and overall (HR 1.63, 95% CI 0.98–2.71) survival. High-repair outcomes were also significantly worse compared with the L1 and L2 groups. HCCs vary in DNA repair expression, and a subset of tumors with high regeneration profoundly disrupts liver biology and poor prognosis.