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Background <p>Germline pathogenic alleles predispose carriers to malignancies; failure to recognize the underlying cancer susceptibility and subsequent delayed diagnosis may lead to severe health impairment. It remains largely undetermined what the somatic mutation characteristics are in colorectal cancer (CRC) patients with pathogenic/likely pathogenic (P/LP) germline mutations and whether, and how, these germline mutations typically located in non-mismatch repair genes, are associated with CRC tumorigenesis.</p> Methods <p>From 8,676 Chinese patients with CRC, we initially screened those who had undergone both germline and somatic mutation testing. We analyzed the relationship between germline mutations and the somatic mutational landscape in this cohort. Germline alterations were examined with a 556- or 105- gene next-generation sequencing panel, and somatic alterations were examined with a 556-gene panel.</p> Results <p>Overall, 80 CRC patients were identified as carriers of P/LP germline mutations. After excluding 6 patients lacking somatic mutation testing data, 74 patients with P/LP germline mutations and 100 patients without germline mutations were finally enrolled in this study. Twenty-one germline genes were detected in the 74 patients. Compared with patients without P/LP mutations (non-P group), those in the P/LP mutations (P group) had significantly lower age and a higher ratio of microsatellite instability. Patients harboring P/LP germline mutations in MMR genes (P-MMR) were significantly younger and more frequently exhibited high tumor mutational burden. The most frequent somatic variations were <i>KRAS</i> and <i>TP53</i>. The somatic mutational landscape revealed a significantly higher mutational frequency in the P group than in the non-P group, and in the P-MMR group than in the P-non-MMR group. The MAPK pathway was significantly enriched in the P and P-MMR groups. Our data showed lower mutation rate of <i>MSH2</i> among all MMR genes than in the Western population. Population-based risk analysis indicated that the odds ratio of <i>BRCA2</i> and <i>ATM</i> mutations exceeded 10.</p> Conclusions <p>Our findings offer a comprehensive overview of genetic susceptibility in Chinese CRC, which may help to shape a more comprehensive understanding of genetic structure of CRC and generate accurate individualized risk management strategies for mutation carriers.</p>

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Genetic landscape of Chinese colorectal cancer: insights into germline and somatic mutations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月10日

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  • Fazhi Zhao,
  • Hexin Lin,
  • Rui Han,
  • Meng Wang,
  • Lin Yang,
  • Dianfeng Tian,
  • Liangqi Zhong,
  • Pengxin Zhang,
  • Queling Liu

摘要

Background

Germline pathogenic alleles predispose carriers to malignancies; failure to recognize the underlying cancer susceptibility and subsequent delayed diagnosis may lead to severe health impairment. It remains largely undetermined what the somatic mutation characteristics are in colorectal cancer (CRC) patients with pathogenic/likely pathogenic (P/LP) germline mutations and whether, and how, these germline mutations typically located in non-mismatch repair genes, are associated with CRC tumorigenesis.

Methods

From 8,676 Chinese patients with CRC, we initially screened those who had undergone both germline and somatic mutation testing. We analyzed the relationship between germline mutations and the somatic mutational landscape in this cohort. Germline alterations were examined with a 556- or 105- gene next-generation sequencing panel, and somatic alterations were examined with a 556-gene panel.

Results

Overall, 80 CRC patients were identified as carriers of P/LP germline mutations. After excluding 6 patients lacking somatic mutation testing data, 74 patients with P/LP germline mutations and 100 patients without germline mutations were finally enrolled in this study. Twenty-one germline genes were detected in the 74 patients. Compared with patients without P/LP mutations (non-P group), those in the P/LP mutations (P group) had significantly lower age and a higher ratio of microsatellite instability. Patients harboring P/LP germline mutations in MMR genes (P-MMR) were significantly younger and more frequently exhibited high tumor mutational burden. The most frequent somatic variations were KRAS and TP53. The somatic mutational landscape revealed a significantly higher mutational frequency in the P group than in the non-P group, and in the P-MMR group than in the P-non-MMR group. The MAPK pathway was significantly enriched in the P and P-MMR groups. Our data showed lower mutation rate of MSH2 among all MMR genes than in the Western population. Population-based risk analysis indicated that the odds ratio of BRCA2 and ATM mutations exceeded 10.

Conclusions

Our findings offer a comprehensive overview of genetic susceptibility in Chinese CRC, which may help to shape a more comprehensive understanding of genetic structure of CRC and generate accurate individualized risk management strategies for mutation carriers.