Distinct Germline Mutation Landscape and Clinical Implications in Chinese Colorectal Cancer: A Large-Scale Genomic...

To investigate the prevalence, characteristics, and clinical implications of germline mutations in a consecutive cohort of Chinese colorectal cancer (CRC) patients, providing insights that may inform population-specific genetic testing strategies.

A total of 1094 CRC patients from two centers were retrospectively analyzed using a 53-gene hereditary cancer panel. Germline variants were classified according to ACMG/AMP guidelines. Clinical characteristics, molecular features, and survival outcomes were examined, and mutation frequencies were compared with published data.

Germline pathogenic/likely pathogenic (P/LP) mutations were identified in 9.3% of patients, with mismatch repair (MMR) genes most frequently affected (4.2%). Higher mutation rates were associated with early-onset CRC, nonmetastatic disease, and a family history of cancer. Compared to Western populations, Chinese patients showed significantly lower frequencies of MUTYH and APC mutations (both 0.4% vs. 2.0%, p < 0.01) but higher rates of MMR mutations. Among the 106 germline variants detected, 63.2% were in NCCN-recommended genes, while 36.8% were found in non-NCCN genes, primarily within homologous recombination repair and Fanconi anemia pathways. Patients harboring germline P/LP mutations had significantly better progression-free survival (HR = 0.52, p < 0.001). Notably, 50.0% of mutation carriers had no family history, and 29.4% were diagnosed after age 65, highlighting the limitations of current criteria-based testing strategies.

This study reveals distinct germline mutation patterns and clinical features in Chinese CRC patients, underscoring the need for population-specific genetic testing and tailored screening to improve prevention, early detection, and personalized treatment in Asian populations.