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. 2022 Jan 12;19(5):707-732.
doi: 10.20892/j.issn.2095-3941.2021.0190.

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

Affiliations

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

Jianfei Yao et al. Cancer Biol Med. .

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: Colorectal cancer; Lynch syndrome; MMR; MSI; Notch signaling pathway; TMB; germline; hereditary cancer; next-generation sequencing.

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Conflict of interest statement

Jianfei Yao, Pan Yang, Xiaohui Wang, Danni Liu, Tanxiao Huang, Huiya Cao, Peisu Suo, and Lele Song are employees of HaploX Biotechnology, and performed the NGS sequencing in this study. The other authors claim no conflicts of interest.

Figures

Figure 1
Figure 1
Category and distribution of germline mutations in the Chinese population. A. The number of mutations in highly mutated genes in the pathogenic (P) and likely pathogenic (LP) groups. B. Details of mutated genes and their numbers in the Lynch syndrome (LS) and non-Lynch syndrome (non-LS) groups.
Figure 1
Figure 1
Category and distribution of germline mutations in the Chinese population. A. The number of mutations in highly mutated genes in the pathogenic (P) and likely pathogenic (LP) groups. B. Details of mutated genes and their numbers in the Lynch syndrome (LS) and non-Lynch syndrome (non-LS) groups.
Figure 2
Figure 2
Types and distribution of mutations in highly mutated genes. A. Types and numbers of germline mutations in the P and LP groups. B. Distribution of P (red) and LP (blue) mutations in highly mutated genes, including APC, ATM, MLH1, MSH2, MSH6, and PMS2. Blue bars indicate key functional domains.
Figure 2
Figure 2
Types and distribution of mutations in highly mutated genes. A. Types and numbers of germline mutations in the P and LP groups. B. Distribution of P (red) and LP (blue) mutations in highly mutated genes, including APC, ATM, MLH1, MSH2, MSH6, and PMS2. Blue bars indicate key functional domains.
Figure 3
Figure 3
Comparison of somatic mutational frequency of highly mutated genes among the P, LP, and non-P groups. A. Comparison of somatic SNV/indel frequency among groups. B. Comparison of somatic CNV frequency among groups. C. Comparison of somatic SNV/indel frequency between patients with and without Lynch-related P germline mutations. D. Comparison of somatic CNV frequency between patients with and without Lynch-related P germline mutations. E. Comparison of TMB among the P, LP, and non-P groups. *P < 0.05; **P < 0.01; ***P < 0.001.
Figure 4
Figure 4
Representative highly significant somatic pathway clustering for the P, LP, and non-P groups. A. GO (biological function, BP) and KEGG somatic pathway clustering results for the groups. B. GO (BP) and KEGG somatic pathway clustering results for patients with or without Lynch P germline mutations.
Figure 4
Figure 4
Representative highly significant somatic pathway clustering for the P, LP, and non-P groups. A. GO (biological function, BP) and KEGG somatic pathway clustering results for the groups. B. GO (BP) and KEGG somatic pathway clustering results for patients with or without Lynch P germline mutations.
Figure 4
Figure 4
Representative highly significant somatic pathway clustering for the P, LP, and non-P groups. A. GO (biological function, BP) and KEGG somatic pathway clustering results for the groups. B. GO (BP) and KEGG somatic pathway clustering results for patients with or without Lynch P germline mutations.
Figure 4
Figure 4
Representative highly significant somatic pathway clustering for the P, LP, and non-P groups. A. GO (biological function, BP) and KEGG somatic pathway clustering results for the groups. B. GO (BP) and KEGG somatic pathway clustering results for patients with or without Lynch P germline mutations.
Figure 4
Figure 4
Representative highly significant somatic pathway clustering for the P, LP, and non-P groups. A. GO (biological function, BP) and KEGG somatic pathway clustering results for the groups. B. GO (BP) and KEGG somatic pathway clustering results for patients with or without Lynch P germline mutations.

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