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Original Article | Open Access

Comprehensive characterization of CRC with germline mutations reveals a distinct somatic mutational landscape and elevated cancer risk in the Chinese population

Jianfei Yao1,2,*, Yunhuan Zhen3,*, Jing Fan4, Yuan Gong5, Yumeng Ye6, Shaohua Guo7, Hongyi Liu7, Xiaoyun Li3, Guosheng Li3, Pan Yang2, Xiaohui Wang2, Danni Liu2, Tanxiao Huang2, Huiya Cao2, Peisu Suo2, Yuemin Li1, Jingbo Yu8, Lele Song1,2,9
Department of Radiotherapy, the Eighth Medical Center of the Chinese PLA General Hospital, Beijing 100091, China
HaploX Biotechnology, Shenzhen 518057, China
Department of Colorectal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
International Business School, Beijing Foreign Studies University, Beijing 100089, China
Department of Gastroenterology, the Second Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing 100850, China
Department of General Surgery, the First Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
Department of Hepatobiliary Surgery, Dalian Municipal Central Hospital, Dalian Medical University, Dalian 116033, China
Comprehensive Liver Cancer Department, the Fifth Medical Center of the Chinese PLA General Hospital, Beijing 100039, China

* These authors contributed equally to this work.

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Abstract

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.

Keywords

next-generation sequencingColorectal cancergermlineLynch syndromehereditary cancerNotch signaling pathwayTMBMSIMMR

Electronic Supplementary Material

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Cancer Biology & Medicine
Volume 19 Issue 5,
May 2022
Pages 707-732
DOI: 10.20892/j.issn.2095-3941.2021.0190
Cite this article:
Yao J, Zhen Y, Fan J, et al. Comprehensive characterization of CRC with germline mutations reveals a distinct somatic mutational landscape and elevated cancer risk in the Chinese population. Cancer Biology & Medicine, 2022, 19(5): 707-732. https://doi.org/10.20892/j.issn.2095-3941.2021.0190

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Received: 24 March 2021
Accepted: 16 July 2021
Published: 24 June 2022
©2022 Cancer Biology & Medicine.

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