Mutational profiles of hepatocellular carcinoma that arose in outbred mice after heavy-ion particle and γ-ray radiation

Cancer risk estimation from space radiation is challenged by the lack of relevant experimental and epidemiological data for human exposure to the high-charge, high-energy (HZE) ions that predominate in deep space environments. Genetically diverse outbred mice provide an effective model for simulating HZE radiation-induced cancers in humans. A previous study using this model revealed a broad spectrum of cancer histotypes linked to various types of ionizing radiation, with hepatocellular carcinoma (HCC) emerging as one of the most prevalent solid tumors following HZE ion exposure. To identify the mutational profiles of radiogenic HCC in outbred mice, whole genome sequencing was performed on radiation-associated HCC samples and compared to profiles from spontaneous HCC cases. The analysis revealed both shared genomic features and distinct characteristics associated with different radiation types. These included tumor mutation burden (TMB), mutational signatures, and regions of hypermutation. β-catenin ( Ctnnb1 ), a gene commonly linked to non-viral, well-differentiated human HCC, was found to be among the most frequently mutated genes in radiation-associated HCCs, whereas a significantly lower mutation frequency of Ctnnb1 observed in spontaneous tumors. Additionally, a chromosomal structural variant affecting the Cdk6 gene was identified in HZE-irradiated tumor samples. These findings suggest the presence of unique genomic features associated with radiogenic HCC, some of which are specifically linked to HZE radiation-induced tumors. The results provide valuable insights into the potential mechanisms underlying radiation-induced liver cancer and offer translational relevance for assessing human cancer risk during spaceflight.