Characterizing the Mutational Landscape of In-Transit Melanoma Metastases

In-transit melanoma (ITM) is a unique presentation of metastatic cutaneous melanoma associated with therapeutic challenges. Despite its clinical importance, the molecular drivers of ITM remain poorly defined. We aimed to characterize the mutational landscape of ITM and identify genetic alterations distinguishing it from other melanoma metastases. Tumor samples from 528 patients in the MSK-IMPACT dataset, comprised of over 300 cancer-related genes, were analyzed. Samples were classified as primary, in-transit, regional lymph node, or distant metastases. Driver mutation frequencies were compared across groups, and mutual information (MI) and principal component analysis (PCA) were used to identify ITM-associated genes and mutation patterns. NRAS Q61 mutations were enriched in ITM compared with other melanoma sites, while NF1 mutations were less common. Exploratory MI, PCA, and pairwise analyses identified recurrent NRAS^MUT/wild-type gene patterns that may distinguish ITM from other melanoma samples. Genes retained in the wild-type state alongside NRAS^MUT were associated with PI3K/AKT/mTOR, TGF-β, and E2F-related pathways. Collectively, these findings suggest that ITM is enriched for NRAS Q61 mutations and may have a comparatively lower co-mutation burden, providing a basis for future studies of ITM biology and clinical behavior.