Tumors with mutations in chromatin regulators are associated with higher mutational burden and improved response to checkpoint immunotherapy

Abstract

In recent years, it has been demonstrated that many of the pervasive genetic defects throughout cancerogenesis occur in genes encoding chromatin regulators (CRs). We analyzed the distribution and characteristics of well-studied CRs across tens of thousands of tumor samples. Our analysis revealed that tumors with mutations in CRs are associated with high tumor mutational burden (TMB). The co-occurrence of mutations in multiple CRs was linked with a further increase in TMB. Given that TMB may predict the clinical response to immune checkpoint inhibitor (ICI) treatment, we investigated the relationship between mutations in CRs and ICI response. We found that patients harboring mutations in CRs exhibited improved responses to ICI treatment, comparable to those with deficiencies in canonical DNA repair pathways. Overall, this study uncovered significant relationships between mutations in chromatin regulators and critical features of cancer, underscoring the need for further functional and clinical studies.