DNA Damage Repair Gene Set as a Potential Biomarker for Stratifying Patients with High Tumor Mutational Burden

SIMPLE SUMMARY: Immunotherapy has been a promising therapeutic approach for cancer treatment in recent years. Although cancer immunotherapy has achieved remarkable success, treatment response is only observed in a small number of patients. As nonresponders need to endure high treatment costs and toxicities with little benefit from treatment, identifying potential predictive biomarkers is critical to optimize the benefits of immunotherapy in patients. The total number of mutations in the tumor genome is a useful biomarker. Patients with a large number of mutations tend to respond better to cancer immunotherapy. However, assessment of the total number of mutations may not be easy. In this study, we identified gene sets with only a small number of genes whose mutations serve as an indicator of the total number of mutations. These cancer-specific gene sets can be used as a cost-effective approach to stratify patients with a large number of mutations in clinical practice. ABSTRACT: Tumor mutational burden (TMB) is a promising predictive biomarker for cancer immunotherapy. Patients with a high TMB have better responses to immune checkpoint inhibitors. Currently, the gold standard for determining TMB is whole-exome sequencing (WES). However, high cost, long turnaround time, infrastructure requirements, and bioinformatics demands have prevented WES from being implemented in routine clinical practice. Panel-sequencing-based estimates of TMB have gradually replaced WES TMB; however, panel design biases could lead to overestimation of TMB. To stratify TMB-high patients better without sequencing all genes and avoid overestimating TMB, we focused on DNA damage repair (DDR) genes, in which dysfunction may increase somatic mutation rates. We extensively explored the association between the mutation status of DDR genes and TMB in different cancer types. By analyzing the mutation data from The Cancer Genome Atlas, which includes information for 33 different cancer types, we observed no single DDR gene/pathway in which mutation status was significantly associated with high TMB across all 33 cancer types. Therefore, a computational algorithm was proposed to identify a cancer-specific gene set as a surrogate for stratifying patients with high TMB in each cancer. We applied our algorithm to skin cutaneous melanoma and lung adenocarcinoma, demonstrating that the mutation status of the identified cancer-specific DDR gene sets, which included only 9 and 14 genes, respectively, was significantly associated with TMB. The cancer-specific DDR gene set can be used as a cost-effective approach to stratify patients with high TMB in clinical practice.