DNA Damage Repair Profiles Alteration Characterize a Hepatocellular Carcinoma Subtype With Unique Molecular and Clinicopathologic Features

Hepatocellular carcinoma (HCC) is one of the most common malignancies and displays high heterogeneity of molecular phenotypes. We investigated DNA damage repair (DDR) alterations in HCC by integrating multi-omics data. HCC patients were classified into two heterogeneous subtypes with distinct clinical and molecular features: the DDR-activated subtype and the DDR-suppressed subtype. The DDR-activated subgroup is characterized by inferior prognosis and clinicopathological features that result in aggressive clinical behavior. Tumors of the DDR-suppressed class, which have distinct clinical and molecular characteristics, tend to have superior survival. A DDR subtype signature was ultimately generated to enable HCC DDR classification, and the results were confirmed by using multi-layer date cohorts. Furthermore, immune profiles and immunotherapy responses are also different between the two DDR subtypes. Altogether, this study illustrates the DDR heterogeneity of HCCs and is helpful to the understanding of personalized clinicopathological and molecular mechanisms responsible for unique tumor DDR profiles.

Automated summary

Hepatocellular carcinoma (HCC) shows high heterogeneity in DNA damage repair (DDR) alterations, with patients classified into DDR-activated and DDR-suppressed subtypes based on distinct clinical and molecular features. DDR-activated subtype has inferior prognosis and aggressive clinical behavior, while DDR-suppressed class exhibits superior survival. The study also reveals different immune profiles and immunotherapy responses between the two DDR subtypes.