Prevalence and clinical relavance of germline mutations in Chinese patients with pancreatic cancer

Cell Commun Signal. 2025 Jun 21;23(1):300. doi: 10.1186/s12964-025-02281-1.

Abstract

Introduction: The prevalence and clinical significance of germline sequence variations in unselected Chinese pancreatic cancer (PC) patients remain underexplored.

Methods: This retrospective study analyzed PC patients (not selected for age or family history) who underwent germline cancer predisposition gene analysis from January 2019 to December 2023 at Ruijin Hospital. Comparative data were sourced from The Genome Aggregation Database (gnomAD) and the China Metabolic Analytics Project (ChinaMAP) database. Germline P/LP variants were classified using MSK's Precision Oncology Knowledge Base, and their clinical relevance and potential for genotype-directed therapy were evaluated.

Results: Sequencing of 1812 unselected Chinese PC cases (1088 [60.0%] male; mean [SD] age, 65.3 [9.5] years) identified 185 pathogenic and Likely pathogenic germline variants (P/LP GVs) in 174 patients (9.3%, 95% CI 8.0%-10.7%), with 43.1% affecting known pancreatic cancer susceptibility genes. Patients with P/LP GVs were diagnosed 2.68 years younger (p < 0.001) than those without. Besides the known PC predisposition genes, DNMT3A emerge as novel potential susceptibility genes for PC. OncoKB classification showed 54.0% had P/LP GVs with therapeutic implications, occurring in 94 out of 1,812 (5.2%) Chinese PC patients. Collectively, P/LP GVs in homologous recombination genes constituted 95.7% (n = 90) of all therapeutically actionable GVs. After adjustment, patients with P/LP GVs exhibited significantly improved overall survival (OS) than those without (HR = 0.7107, 95% CI: 0.5390-0.9373, p = 0.0156). Among patients with P/LP GVs, 119 had de novo metastases. Those with OncoKB level 1 variants had better OS than those without. Additionally, patients received genotype directed chemo or targeted therapies had much better improved survival.

Conclusion: In this cohort, 5.2% of PC patients possessed therapeutically relevant P/LPGVs. Germline testing may provide prognostic benefits and is crucial for therapy selection, particularly in metastatic PC patients.

Keywords: Cancer predisposition gene; Genotype directed therapy; Germline mutation; Pancreatic cancer; Therapeutically actionable germline variant.

MeSH terms

  • Aged
  • Asian People* / genetics
  • China / epidemiology
  • East Asian People
  • Female
  • Genetic Predisposition to Disease
  • Germ-Line Mutation* / genetics
  • Humans
  • Male
  • Middle Aged
  • Pancreatic Neoplasms* / epidemiology
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / pathology
  • Prevalence
  • Retrospective Studies

Supplementary concepts

  • Chinese people