No abstract

Objective: Hereditary colorectal cancer (CRC) accounts for approximately 5%–10% of all CRC cases. The full profile of CRC-relatedgermline 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) Chinesepatients with CRC and examined their relationship with the somatic mutational landscape. Germline alterations were examined witha 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 mutationswere identified in 62 patients, accounting for 7.6% (147/1,923) of all patients. MSH2 and APC was the most mutated gene in theLynch syndrome and non-Lynch syndrome groups, respectively. Patients with P/LP mutations had a significantly higher ratio ofmicrosatellite 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-Pgroup. 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 syndromegroup, and the MAPK and cAMP signaling pathways were uniquely clustered in the non-Lynch syndrome group. Population riskanalysis 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) forthe LP group. Conclusions: Distinct features were revealed in Chinese patients with CRC with germline mutations. The Notch signaling pathwaywas uniquely clustered in the Lynch syndrome group, and the MAPK and cAMP signaling pathways were uniquely clustered in thenon-Lynch syndrome group. Patients with P/LP germline mutations exhibited higher CRC risk.