RT Journal Article SR Electronic T1 Comprehensive characterization of CRC with germline mutations reveals a distinct somatic mutational landscape and elevated cancer risk in the Chinese population JF Cancer Biology & Medicine JO Cancer Biology & Medicine FD China Anti-Cancer Association SP 707 OP 732 DO 10.20892/j.issn.2095-3941.2021.0190 VO 19 IS 5 A1 Jianfei Yao A1 Yunhuan Zhen A1 Jing Fan A1 Yuan Gong A1 Yumeng Ye A1 Shaohua Guo A1 Hongyi Liu A1 Xiaoyun Li A1 Guosheng Li A1 Pan Yang A1 Xiaohui Wang A1 Danni Liu A1 Tanxiao Huang A1 Huiya Cao A1 Peisu Suo A1 Yuemin Li A1 Jingbo Yu A1 Lele Song YR 2022 UL http://www.cancerbiomed.org/content/19/5/707.abstract AB Objective: Hereditary colorectal cancer (CRC) accounts for approximately 5%–10% of all CRC cases. The full profile of CRC-related germline mutations and the corresponding somatic mutational profile have not been fully determined in the Chinese population.Methods: We performed the first population study investigating the germline mutation status in more than 1,000 (n = 1,923) Chinese patients with CRC and examined their relationship with the somatic mutational landscape. Germline alterations were examined with a 58-gene next-generation sequencing panel, and somatic alterations were examined with a 605-gene panel.Results: A total of 92 pathogenic (P) mutations were identified in 85 patients, and 81 likely pathogenic (LP) germline mutations were identified in 62 patients, accounting for 7.6% (147/1,923) of all patients. MSH2 and APC was the most mutated gene in the Lynch syndrome and non-Lynch syndrome groups, respectively. Patients with P/LP mutations had a significantly higher ratio of microsatellite instability, highly deficient mismatch repair, family history of CRC, and lower age. The somatic mutational landscape revealed a significantly higher mutational frequency in the P group and a trend toward higher copy number variations in the non-P group. The Lynch syndrome group had a significantly higher mutational frequency and tumor mutational burden than the non-Lynch syndrome group. Clustering analysis revealed that the Notch signaling pathway was uniquely clustered in the Lynch syndrome group, and the MAPK and cAMP signaling pathways were uniquely clustered in the non-Lynch syndrome group. Population risk analysis indicated that the overall odds ratio was 11.13 (95% CI: 8.289–15.44) for the P group and 20.68 (95% CI: 12.89–33.18) for the LP group.Conclusions: Distinct features were revealed in Chinese patients with CRC with germline mutations. The Notch signaling pathway was uniquely clustered in the Lynch syndrome group, and the MAPK and cAMP signaling pathways were uniquely clustered in the non-Lynch syndrome group. Patients with P/LP germline mutations exhibited higher CRC risk.