Association between germline DNA damage repair-related genes mutation and tumor mutational burden in lung cancer patients

e21163 Background: Deleterious somatic DNA damage repair (DDR) gene mutations are frequent in non-small cell lung cancer (NSCLC) and are associated with improved clinical outcomes of immunotherapy. DDR gene mutations are associated with higher tumor mutational burden (TMB) in cancer. However, the effect of germline DDR-related genes mutation with different functional annotations on TMB in NSCLC patients is still unclear. Methods: 1671 Chinese patients with NSCLC were enrolled in this study. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples or peripheral blood by next generation sequencing (NGS) with 733 cancer-related genes panel. The germline mutation data were obtained. All annotations in clinical significance were according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Results: 1076 patients (64.39%) had germline DDR-related gene mutations and 595 (35.61%) had no germline DDR-related gene mutations. Among patients with DDR-related gene mutations, 78 (7.25%) patients had the pathogenic (P) mutations or likely pathogenic (LP) mutations and 1056 (98.14%) had variants of unknown significance (VOUS) mutations. In total, the median TMB was 3.91 mutations/MB (range, 0-68.16) and 4.47 mutations/MB (range, 0-51.40) in patients with P, LP or VOUS mutations and no germline DDR-related gene mutations, respectively. To the further analysis, we divided patients with germline DDR-related gene mutations into three groups: only P or LP mutations (Group 1), only VOUS mutations (Group 2) and concurrence with P/LP/VOUS mutations (Group 3). Compare to the DDR-negative group, TMB was significantly lower in Group 2 (P < 0.001). No significant differences in Group 1 and Group 3 were observed. In addition, we found that mutations in different DDR pathway could not affect TMB value significantly. Conclusions: Germline DNA damage repair-related genes mutation may be not associated with TMB.