Cancer type-specific profiling of chromatin regulator mutations identifies recurrent and co-occurring gene sets associated with improved survival following immune checkpoint therapy

Mutations in chromatin regulator (CR) genes are frequent across human cancers and have been associated with increased tumor mutational burden (TMB) and improved response to immune checkpoint inhibitor (ICI) treatment. Here, using discovery and independent validation cohorts, we resolved these associations at the level of individual cancer types and investigated whether shared CR mutation patterns emerge across colorectal cancer, melanoma, renal cell carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, bladder cancer, esophagogastric cancer, pancreatic adenocarcinoma, prostate cancer, and breast cancer. For each cancer type, we identified a distinct set of pro-survival CR genes, whose mutations were associated with improved survival following ICI treatment. We further identified a subset of recurrent CRs that were associated with improved ICI outcomes across many cancer types, although the magnitude of the association varied between cancers. Co-occurrence of mutations in two or more CRs was associated with further improvement in survival, while several individual CR genes showed particularly robust associations with favorable ICI outcomes. Across cancer types, CR-altered groups consistently displayed higher TMB than their corresponding CR-unaltered groups. Transcriptomics-based deconvolution further revealed cancer-type-specific differences in the tumor microenvironment associated with CR mutations. Together, these findings demonstrate both cancer-specific and recurrent patterns of CR mutations associated with improved outcomes following ICI treatment and further establish a relationship between CR alterations, increased TMB, and ICI response.