Jiang Yu, Li Dan, Liu Yang, Qin Jiejie, Chen Hao, Zhang Jun, Gu Yijin, Shen Baiyong, Jin Jiabin
Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Pancreatic Neoplasms Translational Medicine, Shanghai, China.
Cell Commun Signal. 2025 Jun 21;23(1):300. doi: 10.1186/s12964-025-02281-1.
The prevalence and clinical significance of germline sequence variations in unselected Chinese pancreatic cancer (PC) patients remain underexplored.
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.
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.
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.
在中国未经过筛选的胰腺癌（PC）患者中，生殖系序列变异的患病率及其临床意义仍未得到充分研究。
这项回顾性研究分析了2019年1月至2023年12月在瑞金医院接受生殖系癌症易感基因分析的PC患者（未根据年龄或家族史进行筛选）。比较数据来自基因组聚合数据库（gnomAD）和中国代谢分析项目（ChinaMAP）数据库。使用纪念斯隆凯特琳癌症中心（MSK）的精准肿瘤知识库对生殖系致病性/可能致病性变异进行分类，并评估其临床相关性以及基因型导向治疗的潜力。
对1812例未经过筛选的中国PC病例（1088例[60.0%]为男性；平均[标准差]年龄为65.
