Analysis of ATM germline mutations in solid tumors from Chinese patients.

10586 Background: Ataxia-telangiectasia mutated (ATM) is a tumor suppressor genes and plays an important role in the repair of DNA double-strand breaks (DSBs). Germ-line mutations of ATM gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Novel therapies are in development that may improve the response to therapy of patients with ATM-deficient cancers including targeted therapy and immunotherapy. Nevertheless, the knowledge of incidence of ATM germline mutations in solid tumor remains poorly understood. Methods: We identified 19248 malignant solid tumors patients without selecting age or family history in a retrospective cohort. The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines.The patients were divided into two groups, P/ LP group (with pathogenic or likely-pathogenic mutations), and Non-P/LP group (neither pathogenic nor likely-pathogenic mutation). Results: In 19248 patients with pan-cancer, 76 patients were found 76 heterozygous pathogenic or likely pathogenic germline mutations in ATM gene and the mutation frequency was 0.39%.Among these 76 carriers, 71 (93.4%) carried frameshift, nonsense or splice mutations (33 for frameshift,21 for missense and 17 for splice mutations). 4 carried missense mutations and 1 carried intron mutations. Eliminated a few types of cancers that had a smaller number (less than 50), the higher frequency of mutations contained cancers were pancreatic cancer (1.0%,7/692), breast cancer (0.71%,3/423), gastric cancer (0.6%,7/1094), The median age of group P/LP and non-P/LP group was 64 and 63 in pancreatic cancer，62 and 53 in breast cancer and 62 and 61 in gastric cancer. The three genes with the most somatic mutations were TP53, MUC16 and KRAS in P/LP group and were TP53, MUC16 and EGFR in non-P/LP group. There was no significant difference in mutation frequency of the four genes. The media TMB in P/LP group and non-P/LP group were 3.55 and 2.84 respectively and there was no statistical difference. In P/LP group，only one patients is high microsatellite instability who carryied a MLH1 and a ATM pathogenic mutation. Conclusions: This was the first report of the incidence of ATM germline mutations in Chinese solid tumors which expanded the understanding of ATM and provided a direction for clinical trial design of novel therapies. The relationship between germline mutations and cancer susceptibility will be studied in the future.