A new study published in BMC Genomics by Liang-Hao Ding of The University of Texas Health Science Center at Tyler and UT Southwestern Medical Center, together with Michael D. Story, Shoukath Sulthana, R Burke Squires, Elijah F. Edmondson, Michael M. Weil and colleagues, addresses this question at the level of whole genomes. The team performed whole genome sequencing on hepatocellular carcinoma (HCC), the most common form of primary liver cancer, that arose in mice after exposure to heavy-ion particle radiation or gamma-ray radiation, and compared the resulting mutational profiles with those of spontaneously arising liver tumors. Their goal was to identify genomic features that could serve as fingerprints of radiogenic cancer, and in particular of cancers caused by the HZE ions that dominate the deep-space radiation field.

The choice of experimental model is a critical part of the study’s design. Laboratory cancer experiments have traditionally relied on inbred mouse strains, which offer genetic uniformity but poorly reflect the genetic heterogeneity of human populations. In this work, the researchers used outbred mice, whose genomes carry a broad mosaic of genetic variants similar to the diversity seen in humans. This genetically diverse background provides a more realistic substrate for tumor development, allowing cancers to emerge through the interplay of random mutations, environmental insults and individual genetic susceptibility. An earlier study using the same model had already revealed a wide spectrum of cancer histotypes linked to different types of ionizing radiation, with hepatocellular carcinoma emerging as one of the most prevalent solid tumors following HZE ion exposure. That observation made radiation-associated HCC a natural target for deeper genomic interrogation.

The sequencing effort focused on three complementary layers of genomic information. The first was tumor mutation burden, or TMB, the total number of somatic mutations accumulated in a tumor’s genome. Mutation burden is a coarse but informative metric: radiation, particularly high linear energy transfer (LET) radiation, tends to inflict dense, clustered DNA damage that can elevate mutation counts above what spontaneous processes produce. The second layer was mutational signatures, the characteristic patterns of base substitutions and other mutation types that different mutagenic processes imprint on the genome. Just as forensic scientists match bullets to specific weapons, cancer geneticists decompose a tumor’s mutation catalogue into signatures attributable to specific causes, from ultraviolet light to tobacco smoke to defective DNA repair. The third layer comprised regions of hypermutation, localized stretches of the genome where mutations cluster at rates far exceeding the background, often marking sites of catastrophic or localized DNA damage and repair.

Across these layers, the analysis revealed both shared genomic features and distinct characteristics associated with the different radiation types. Radiation-associated tumors differed from spontaneous ones in their mutation burdens, their signature compositions and their hypermutation landscapes, and within the radiation-exposed group there were features that separated HZE-induced tumors from gamma-ray-induced ones. This distinction matters scientifically because gamma rays, as low-LET photons, produce sparse ionizations similar to X-rays, whereas HZE ions produce dense ionization tracks. If the genomic consequences of these two exposure types can be reliably separated, it opens the possibility of reading a tumor’s genome as a dosimeter of sorts, inferring not just that radiation played a role in its genesis but which kind of radiation was responsible.

One of the most striking findings concerns the gene Ctnnb1, which encodes beta-catenin, a central component of the Wnt signaling pathway that governs cell proliferation, differentiation and liver homeostasis. In human medicine, activating mutations in CTNNB1 are a well-known hallmark of non-viral, well-differentiated hepatocellular carcinoma, and they carry prognostic and diagnostic significance. In the mouse study, beta-catenin emerged as one of the most frequently mutated genes in the radiation-associated HCCs, mirroring its prominence in the human disease. By contrast, the spontaneous tumors showed a significantly lower frequency of Ctnnb1 mutation. This asymmetry suggests that radiation-driven liver carcinogenesis in this model converges on the same beta-catenin pathway that human non-viral HCC commonly exploits, while spontaneous tumors in these mice take other routes to malignancy. The convergence strengthens the translational relevance of the model, indicating that the radiation-induced mouse tumors recapitulate a molecular feature of the human cancers that mission planners ultimately care about.

The study also uncovered a chromosomal structural variant affecting the Cdk6 gene specifically in tumors from HZE-irradiated animals. CDK6 is a cyclin-dependent kinase that drives progression through the G1 phase of the cell cycle, and its dysregulation through amplification, translocation or altered regulation is a recognized mechanism of unchecked proliferation in several human cancers. Structural variants of this kind, which rearrange chromosomal segments rather than simply altering single DNA bases, are precisely the type of damage expected from the clustered, complex DNA breaks that dense ionization tracks produce. When a high-charge particle traverses the double helix, it can generate multiple breaks in close proximity, and the cell’s repair machinery, in stitching the fragments back together, can join the wrong ends, producing deletions, inversions, translocations and other rearrangements. Finding a Cdk6-affecting structural variant in the HZE group, and not in the comparison tumors, is consistent with this mechanistic picture and provides a candidate marker of heavy-ion exposure.

The broader implications of the work extend in two directions. For radiation biology, the results suggest that radiogenic hepatocellular carcinoma possesses unique genomic features, some of which are specifically tied to HZE radiation, offering a mechanistic window into how dense ionization tracks sculpt the cancer genome differently from sparse ionizations. For spaceflight risk assessment, the findings carry direct translational relevance. NASA’s cancer risk models for astronauts currently rest on thin empirical foundations, because epidemiological data for human HZE exposure are essentially limited to occupational cohorts such as atomic bomb survivors and radiation workers, whose exposures were predominantly low-LET. Experimental systems like the outbred mouse model used here, funded through NASA’s Specialized Center of Research on Radiation Carcinogenesis (NSCOR) program, help fill that gap by generating tumors under controlled, space-relevant exposure conditions and by supplying the genomic data needed to validate or refine risk extrapolations from mice to humans.

The technical infrastructure behind the study is also worth noting. Whole genome sequencing of multiple tumors, particularly from outbred animals whose reference-guided read alignment is complicated by genetic diversity, demands substantial computational resources. The authors acknowledge the support of the BioHPC facility at UT Southwestern and the Texas Advanced Computing Center, as well as the NASA Space Radiation Laboratory, where the radiation exposures were delivered. The work was funded by the NASA NSCOR programs under award NNX15AK13G, and all animal procedures were approved by the Colorado State University Institutional Animal Use and Care Committee. The article, published open access on 30 September 2026, was received in June 2025 and accepted in August 2026, reflecting the extended timeline typical of large-scale sequencing studies.

As human spaceflight moves from low Earth orbit toward the Moon and eventually Mars, the stakes of radiation carcinogenesis research rise accordingly. A round trip to Mars could expose crew members to doses and radiation qualities for which no human epidemiological data exist, and liver cancer, as this study shows, is among the malignancies that heavy-ion exposure promotes in a genetically diverse mammalian model. The mutational fingerprints described by Ding and colleagues, from elevated tumor mutation burdens and distinctive signatures to hypermutation regions, frequent beta-catenin mutation and HZE-specific structural variants affecting Cdk6, provide both a mechanistic foundation and a practical toolkit. If future studies confirm that these features reliably distinguish radiation-induced tumors, clinicians and researchers could one day examine a tumor’s genome and infer the radiation quality behind it, while mission designers could use the same knowledge to build more accurate cancer risk models and to develop shielding and countermeasure strategies grounded in the actual genomic consequences of the radiation astronauts will face.

Subject of Research: Mutational profiles of radiation-induced hepatocellular carcinoma in outbred mice exposed to heavy-ion and gamma-ray radiation

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

Article References: Ding, L.-H., Story, M. D., Sulthana, S., Squires, R. B., Edmondson, E. F., & Weil, M. M. (2026). Mutational profiles of hepatocellular carcinoma that arose in outbred mice after heavy-ion particle and γ-ray radiation. BMC Genomics. https://doi.org/10.1186/s12864-026-13304-7

Image Credits: AI Generated

DOI: 10.1186/s12864-026-13304-7

Keywords: space radiation, HZE ions, hepatocellular carcinoma, whole genome sequencing, mutational signatures, tumor mutation burden, beta-catenin, Cdk6, outbred mice, radiation carcinogenesis, liver cancer, NASA