Pathogenic germline variants in Chinese pancreatic adenocarcinoma patients

作者：Xiaoyi Yin, Hui Shen, Huan Wang, Qingchen Wang, Shan Zhang, Chunming Zhang, Qi Jia, Shiwei Guo, Xiongfei Xu, Wenhui Zhang, Bo Li, Xiaohan Shi, Suizhi Gao, Meilong Shi, Xuenan Zhao, Sheng Wang, Jiawei Han, Guoxiao Zhang, Yikai Li, Penghao Li, Wei Jing, Bin Song, Kailian Zheng, Gang Li, Yijie Zhang, Hui Jiang, Cong Wu, Zhijian Song, Gang Niu, Qiangzu Zhang, Jianglong Guo, Zhenjun Sun, Fengxian Han, Yunguang Li, Dong Gao, Haojie Jin, Hongbo Yang, Jing Li, Gang Jin · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-57520-3 · 被引用次数：4 · 研究领域：Pancreatic and Hepatic Oncology Research、Cancer Genomics and Diagnostics、Epigenetics and DNA Methylation

Putting pancreatic adenocarcinoma (PAAD) screening into perspective for high-risk individuals could significantly reduce cancer morbidity and mortality. Previous studies have profiled somatic mutations in PAAD. In contrast, the prevalence of mutations in PAAD predisposition genes has not been defined, especially in the Asian population. Using a multi-tier cohort design and whole genome/exome sequencing, we create a comprehensive germline mutation map of PAAD in 1,123 Chinese cancer patients in comparison with 11 pan-ethnic studies. For well-known pathogenic/likely pathogenic germline variants, Chinese patients exhibit overlapping but distinct germline mutation patterns comparing with Western cohorts, highlighted by lower mutation rates in known PAAD genes including BRCA1, BRCA2, ATM, CDKN2A, and CHEK2, and distinct mutations in CFTR, RAD51D, FANCA, ERCC2, and GNAS exclusive to Chinese patients. CFTR emerges as a top candidate gene following loss of heterozygosity analysis. Using an integrative multi-omics and functional validation paradigm, we discover that deleterious variants of uncertain significance may compromise CFTR’s tumor suppressor function, and demonstrate the clinical relevance by using patient derived organoids for drug screen. Our multifaceted approach not only deepens the knowledge of population differences in PAAD germline mutations but also unveils potential avenues for targeted therapeutic interventions. The prevalence of mutations that can predispose to pan...