PT  - JOURNAL ARTICLE
AU  - Yao, Jianfei
AU  - Zhen, Yunhuan
AU  - Fan, Jing
AU  - Gong, Yuan
AU  - Ye, Yumeng
AU  - Guo, Shaohua
AU  - Liu, Hongyi
AU  - Li, Xiaoyun
AU  - Li, Guosheng
AU  - Yang, Pan
AU  - Wang, Xiaohui
AU  - Liu, Danni
AU  - Huang, Tanxiao
AU  - Cao, Huiya
AU  - Suo, Peisu
AU  - Li, Yuemin
AU  - Yu, Jingbo
AU  - Song, Lele
TI  - Comprehensive characterization of CRC with germline mutations reveals a distinct somatic mutational landscape and elevated cancer risk in the Chinese population
AID  - 10.20892/j.issn.2095-3941.2021.0190
DP  - 2022 May 15
TA  - Cancer Biology & Medicine
PG  - 707--732
VI  - 19
IP  - 5
4099  - http://www.cancerbiomed.org/content/19/5/707.short
4100  - http://www.cancerbiomed.org/content/19/5/707.full
SO  - Cancer Biology & Medicine2022 May 15; 19
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.