Yu Jiang, Dan Li, Yang Liu, Jiejie Qin, Hao Chen, Jun Zhang, Yijin Gu, Baiyong Shen, Jiabin Jin
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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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>In this cohort, 5.2% of PC patients possessed therapeutically relevant P/LPGVs. 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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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>In this cohort, 5.2% of PC patients possessed therapeutically relevant P/LPGVs. 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引用次数: 0
摘要
在未选择的中国胰腺癌（PC）患者中，种系序列变异的患病率和临床意义尚不清楚。方法：本回顾性研究分析了2019年1月至2023年12月瑞金医院接受生殖系癌易感基因分析的PC患者（未选择年龄或家族史）。比较数据来源于基因组聚集数据库（gnomAD）和中国代谢分析项目（ChinaMAP）数据库。使用MSK的精确肿瘤学知识库对生殖系P/LP变异进行分类，并评估其临床相关性和基因型定向治疗的潜力。结果：对1812例未选择的中国PC病例进行测序，其中男性1088例（60.0%）；平均[SD]年龄，65.3[9.5]岁)在174例患者中鉴定出185种致病和可能致病的种系变异（P/LP GVs） （9.3%, 95% CI 8.0%-10.7%），其中43.1%影响已知的胰腺癌易感基因。结论：在该队列中，5.2%的PC患者具有治疗相关的P/LPGVs。生殖系检测可以提供预后益处，对治疗选择至关重要，特别是在转移性PC患者中。
Prevalence and clinical relavance of germline mutations in Chinese patients with pancreatic cancer.
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.
期刊介绍：
Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior.
Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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