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 Yao, Jianfei
A1 Zhen, Yunhuan
A1 Fan, Jing
A1 Gong, Yuan
A1 Ye, Yumeng
A1 Guo, Shaohua
A1 Liu, Hongyi
A1 Li, Xiaoyun
A1 Li, Guosheng
A1 Yang, Pan
A1 Wang, Xiaohui
A1 Liu, Danni
A1 Huang, Tanxiao
A1 Cao, Huiya
A1 Suo, Peisu
A1 Li, Yuemin
A1 Yu, Jingbo
A1 Song, Lele
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.