Mutation profile of DNA damage response genes in Chinese colorectal cancer patients and its association with TMB and MSI.

e15608 Background: DNA damage response (DDR) genes are essential to maintain genomic integrity. Increasing evidence showed that mutations in DDR genes were related to tumor mutation load (TMB), microsatellite instability (MSI) and clinical benefit from immunotherapy. TMB and MSI are predictive biomarkers for immunotherapy. However, the mutation spectrum of genes involved in the DDR pathways and its association with TMB and MSI in Chinese colorectal cancer patients are still ambiguous. Methods: The genomic information of 728 Chinese colorectal cancer patients without germline mutation of Lynch syndrome related genes was obtained from HapLab database. HaploX WESPlus gene panel (an upgraded version of the standard WES) was performed to analyze the genomic data of patients. Results: 630 out of 728 patients (86.54%) had at least one mutation of the DDR genes. The frequently mutated DDR genes included TP53 (54.95%), BRCA2 (18.27%), PARP4 (13.46%), MSH2 (9.62%), XPC (7.55%), RAD54L2 (7.28%), ATM (6.73%), HMGB1 (5.77%), REV3L (5.49%) and POLD3 (5.36%). The TMB in patients with one, two, three and more than three mutations of DDR genes increased sequentially. The proportion of MSI-H in patients with more than three mutations of DDR genes (20.9%) was significantly higher than that in patients with less than 3 mutations of DDR genes (0.38%). Among the frequently mutated DDR genes, mutations of BRCA2, PARP4, MSH2, XPC, RAD54L2, ATM, REV3L or POLD3 were associated with higher TMB, mutations of MSH2, RAD54L2, ATM, REV3L or POLD3 were associated with higher proportion of MSI-H. The patients with mutation in each of eight DDR pathways showed significantly higher TMB and proportion of MSI-H than who without mutation of DDR genes. Conclusions: This study revealed the mutation profile of DDR genes in Chinese colorectal cancer patients. The mutation of DDR genes was closely related to TMB and MSI status. This result indicated the mutation of DDR genes may be a promising biomarker for immunotherapy in Chinese colorectal cancer patients.