Uveal and cutaneous melanoma share a common mutation with distinct prognostic implications: A bioinformatic study

What was known beforeO_LIUveal melanoma (UM) and cutaneous melanoma (CM) arise from a common melanocytic lineage but exhibit distinct genetic landscapes, biological behavior, and clinical outcomes. C_LIO_LIPigmentation-related genes, including IRF4 and HERC2, have been implicated in melanoma susceptibility and prognosis; however, the extent of shared genetic variants between UM and CM has remained unclear. C_LIO_LIPrevious studies have primarily investigated UM and CM separately, leaving limited understanding of their common genetic architecture and potential shared prognostic biomarkers. C_LI What this study addsO_LIThis bioinformatic analysis identified only two shared validated genetic variants between UM and CM across publicly available databases: rs12203592 (IRF4) and rs12913832 (HERC2). C_LIO_LIProtein-protein interaction analysis demonstrated that IRF4 and OCA2 directly interact with HERC2, supporting a biologically plausible pigmentation-related pathway linking the two melanoma subtypes. C_LIO_LIThe findings suggest that IRF4 may represent a common prognostic biomarker across both UM and CM, while combined assessment of IRF4 and HERC2 could improve future risk stratification and facilitate more personalized therapeutic approaches. C_LI BackgroundUveal melanoma (UM) and cutaneous melanoma (CM) both originate from the same cell line. This proposes the possibility of a shared mechanism between entities, requiring explicit investigation. MethodsData from GWAS Catalog and DisGeNET were used to identify shared variation-disease associations (VDAs) between UM and CM. The results were validated using the Ensembl database. In the next step, the STRING database was used to identify the protein- protein interaction. ResultsSubsequently, 109 unique VDAs were identified for UM and 880 for CM. However, only 2 VDAs were found to be shared among UM and CM in different ethnic groups. These shared VDAs were rs12203592 of the IRF4 gene, rs12913832 of the HECT and RLD domain-containing E3 ubiquitin protein ligase 2 (HERC2) gene. Notably, PPI network assessment through STRING showcased that OCA2 and IRF4 directly interacted with HERC2. ConclusionWhile HERC2 acts as a poor prognostic factor in uveal melanoma, IRF4 status is a key prognostic indicator in both UM and CM. Identifying IRF4 allele contributions enables a better understanding of melanoma pathogenesis and fosters the development of disease-specific approaches.