Mutation of DNA damage repair genes confers an immune-privileged tumor microenvironment in colorectal cancer with a prognostic value.

Abstract

4080 Background: Microsatellite instability high (MSI-H)/mismatch-repair-deficient (dMMR) has been proved as a validated biomarker in solid tumors receiving immune checkpoint inhibitors (ICIs). Recently, mutational status of the DNA damage repair (DDR) genes has been linked to anti-tumor immune response in bladder cancer. Therefore, it would be of great interest to unravel the implications of DDR in shaping the immune responsiveness in CRC. Methods: The genomic correlates were examined in a publicly available cohort from Memorial Sloan Kettering Cancer Center (MSK ICI cohort). To explore the associations between DDR mutation and immune features, the genomic data of The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma (COADREAD) dataset was analyzed. Further, we determined DDR mutation and MSI status in a Chinese CRC cohort via a 543-gene panel sequencing. Results: First, we observed that DDR pathway was commonly mutated (21.79%) in the multi-cancer MSK ICI cohort, with the highest frequency of 36.36% in CRCs. Second, survival analysis revealed that the median overall survival (mOS) in patients with DDR mutations was significantly longer than that in the DDR wild-type subgroup, in both pan-cancer (P = 0.0008; mOS 31 vs 16 months) and CRC patients (P = 0.016; mOS 34 vs 13 months) in the MSK ICI cohort. However, in the TCGA COADREAD dataset, there was no significant difference in OS or progression free survival (PFS) between DDR mutant and DDR wild-type subgroups. These observation indicated a specific prognostic value for DDR mutation in patients with ICI treatment while not conventional treatment. Third, in the TCGA COADREAD dataset, DDR mutations were associated with increased TMB, enrichment of immune cell infiltration and immune checkpoint molecule expression, suggesting an improvement of various steps of the cancer immunity cycles in DDR mutant CRCs. Lastly, we investigated the DDR mutational pattern, and its associations with MSI-H and other genomic features in a Chinese CRC cohort. Notably, MSI-H and DDR mutation account for 5.7% and 13.4% respectively, suggesting that DDR may identify a higher proportion of potential responders than MSI-H. Conclusions: Our data suggest that DDR mutation is a potential prognostic biomarker for ICI-treated CRCs. Functional analysis in TCGA dataset revealed that DDR mutation might be an indication of enhanced cancer immunity. The higher incidence of DDR mutation in Chinese CRCs emphasized the future utility of panel-based DDR evaluation in guiding ICI treatment.