Germline variants predictive of tumor mutational burden and immune checkpoint inhibitor efficacy.

ABSTRACT: High tumor mutational burden (TMB) is associated with response to checkpoint blockade in several cancers. We identify pathogenic germline variants associated with increased TMB (GVITMB). GVITMB were found in 7 genes using a pan-cancer approach (APC, FANCL, SLC25A13, ERCC3, MSH6, PMS2, and TP53) and 38 gene sets (e.g., those involved in DNA repair and programmed cell death). GVITMB were also associated with mutational signatures related to the dysfunction of the gene carrying the variant, somatic mutations that further affect the gene or pathway with the variant, or transcriptomic changes concordant with the expected effect of the variant. In a validation cohort of 140 patients with cutaneous melanoma, we found that patients with GVITMB had p

SUBMITTER: Chatrath A 

PROVIDER: S-EPMC7988326 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature