Evaluation of 30 DNA damage response and 6 mismatch repair gene mutations as biomarkers for immunotherapy outcomes across multiple solid tumor types

Objective: DNA damage response (DDR) genes have low mutation rates, which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor (ICI) treatment. Thus, a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy. Methods: A total of 39,631 patients with mutation data were selected from the cBioPortal database. A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center (FUSCC). A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis. A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute (DFCI) cohort were obtained from a published dataset. The Cancer Genome Atlas (TCGA) level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal. Results: Six MMR and 30 DDR genes were included in this study. Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI, and most of them predicted the therapeutic efficacy of ICI, in a manner dependent on TMB, except for 4 combined DDR gene mutations, which were associated with the therapeutic efficacy of ICI independently of the TMB. Single MMR/ DDR genes showed low mutation rates; however, the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high, reaching 10%-30% in several cancer types. Conclusions: Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.