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

Ajay Chatrath; Aakrosh Ratan; Anindya Dutta

doi:10.1016/j.isci.2021.102248

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

iScience. 2021 Mar 4;24(3):102248. doi: 10.1016/j.isci.2021.102248. eCollection 2021 Mar 19.

Authors

Ajay Chatrath¹, Aakrosh Ratan², Anindya Dutta¹

Affiliations

¹ Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, 1240 Pinn Hall, Charlottesville, VA 22908, USA.
² Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.

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 prolonged progression-free survival (p = 0.0349, hazard ratio = 0.688) and responded favorably (p = 0.0341, odds = 1.842) when treated with immune checkpoint inhibitors. Our results suggest that germline variants can influence the molecular phenotypes of tumors and predict the response to immune checkpoint inhibitors.

Keywords: Cancer; Genetics; Genomics.