Mutations in Chromatin Regulator Genes Associate With TMB and Immunotherapy Response in Melanoma.

Melanoma is a high-tumor-mutational-burden (TMB) cancer, largely driven by ultraviolet-induced DNA damage. Although TMB predicts response to immune checkpoint inhibitors (ICIs), the genomic factors underlying its variability remain unclear. In addition to canonical DNA-repair defects such as mismatch repair (MMR) and POLE/POLD1 mutations, alterations in chromatin regulators (CRs) may influence genome stability and mutational load. We analyzed melanoma cohorts from the MSK-ICI, TCGA, MSK-Met, DFCI, and UCLA datasets. TMB was compared between CR-mutant and CR-wild-type tumors and overall cohorts, along with gene-level analyses of individual CRs. Associations between the number of CR mutations and TMB were assessed. Overall survival (OS) in ICI-treated patients was evaluated using Kaplan-Meier and Cox models, with TCGA as a non-ICI-treated comparator. Across datasets, CR-mutant melanomas consistently exhibited significantly higher TMB than CR-wild-type tumors. Several CRs were linked to elevated TMB, comparable to MMR- or POLE/POLD1-mutant tumors. Multiple CR alterations showed a positive linear relationship with TMB. In ICI-treated cohorts, CR-mutant tumors had significantly longer OS, while this link was not observed in non-ICI-treated cases. These findings suggest that CR mutations define a subset of melanomas with high TMB and improved response to ICIs, warranting prospective validation as predictive biomarkers.