The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses.
Zhou Pei,Wu Xueying,Chen Huan,Hu Ying,Zhang Henghui,Wu Lijia,Yang Ying,Mao Beibei,Wang Huaqing
BACKGROUND:Microsatellite-stable (MSS) colon adenocarcinoma (COAD) patients are not sensitive to immune checkpoint inhibitors. Here, we focused on analyzing the relationship between homologous recombination repair (HRR)-related gene mutations and clinical immunotherapy responses in MSS COAD. METHODS:The mutational landscape was profiled in a cohort of 406 Chinese COAD patients via next-generation sequencing (NGS). Correlations between HRR gene mutations and tumor immunity or clinical outcomes in two COAD genomic datasets were analyzed via bioinformatics. RESULTS:In the Chinese cohort, seventy (17%) patients exhibited genomic alterations in HRR genes; (9%), (4%), (3%), (3%) and (3%) were the most frequently mutated. In the MSK-IMPACT COAD cohort (immune checkpoint inhibitor-treated), HRR-mut patients (n=34) survived longer than HRR-wt patients (n=50) (log-rank < 0.01). Based on the TCGA MSS COAD cohort, HRR gene mutations increased immune activities, such as infiltration of cytotoxic cells ( < 0.05) and exhausted CD8+ T cells ( < 0.01), and increased the IFN-γ scores ( < 0.05). The results differed in MSI-H COAD patients (all > 0.05). CONCLUSION:HRR gene mutations significantly increased immune activities in MSS COAD patients, implying the feasibility of the HRR-mut status as an immunotherapy response predictor in MSS COAD.