Dissecting cancer in a non-mammalian model: genomic insights from lemon frost geckos.

Comparative oncology can uncover novel mechanisms of cancer resistance and progression across animals. Non-traditional model organisms with naturally high or low cancer prevalence may provide further insights into metastasis or cancer resistance. In this context, the "lemon frost" morph of the leopard gecko (Eublepharis macularius) shows high prevalence of iridophoromas, exceeding 80%. These tumors can recur and metastasize, presenting a unique opportunity to study pigment cell cancer and tumor progression in a non-mammalian vertebrate. We performed high-coverage whole-genome sequencing on matched tumor and non-tumor samples from three lemon frost individuals. A shared missense mutation in the TATA-box binding protein (TBP) suggests possible disruption to transcriptional regulation in tumor samples. Additionally, a recurrent gene fusion between IARS1 and RNF213 was identified across all tumor samples. Copy number neutral loss of heterozygosity events were observed in three mutated genes that have a role in cancer: MAP3K13, TENM4, and OR2AT4-like, while copy number gains were observed in four genomic regions. Pathway analysis revealed dysregulation in actin filament organization, a hallmark of metastatic potential. These findings suggest a multifaceted genomic basis for tumorigenesis in this model, including transcriptional misregulation, chromatin remodeling defects, and cytoskeletal disruption. This study provides the first characterization of genomic changes associated with iridophoroma in a reptilian species and establishes the lemon frost gecko as a promising model for cancer research. Our findings identify candidate pathways of tumor progression and metastasis in a non-traditional system, highlighting both conserved and novel mechanisms relevant to human disease.