Pathogenic germline variants in Chinese pancreatic adenocarcinoma patients

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.

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Publication Details

Journal
Nature Communications
Published
2025-03-05
DOI
https://doi.org/10.1038/s41467-025-57520-3
Citations
4
Primary Topic
Pancreatic and Hepatic Oncology Research
Type
article
Field-Weighted Citation Impact
4.18
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article

Pathogenic germline variants in Chinese pancreatic adenocarcinoma patients

Guoxiao Zhang, Cong Wu, Haojie Jin, Hui Shen et al.
4 citations
Nature Communications
Pancreatic and Hepatic Oncology Research
4.18
article

Pathogenic germline variants in Chinese pancreatic adenocarcinoma patients

Guoxiao Zhang, Cong Wu, Haojie Jin, Hui Shen, Yunguang Li, Huan Wang, Xiaohan Shi, Mai Shi, Dong Gao, Bin Song, Suizhi Gao, Qingchen Wang, Xiongfei Xu, Qiangzu Zhang, Zhenjun Sun, Penghao Li, Gang Jin, Hongbo Yang, Fenglin Han, Shan Zhang, Jing Li, Bo Li, Gang Li, Yijie Zhang, Wei Jing, Yikai Li, Sheng Wang, Xuenan Zhao, Qi Jia, Gang Niu, Chunming Zhang, Hui Jiang, Xiaoyi Yin, Wenhui Zhang, Shiwei Guo, Jiawei Han, Kailian Zheng, Zhijian Song, Jianglong Guo
article en
4 citations

Abstract

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.

Nature CommunicationsVol. 16(1)
Qingdao University (CN), University of Shanghai for Science and Technology (CN), Second Military Medical University (CN), Shanghai Jiao Tong University (CN), Chinese Academy of Sciences (CN), Renji Hospital (CN), Yuhuangding Hospital (CN), Unimed Medical Institute (CN), People's Liberation Army 401 Hospital (CN), Tongren Hospital (CN), Shanghai Cancer Institute (CN), Changhai Hospital (CN), Center for Excellence in Molecular Cell Science (CN), Eastern Hepatobiliary Surgery Hospital (CN), State Key Laboratory of Oncogene and Related Genes (CN), Obstetrics and Gynecology Hospital of Fudan University (CN), Chinese People's Liberation Army (CN)
Openalex Percentile: Top 6%
Pancreatic and Hepatic Oncology Research
4.18
DOIOpen Access PDFOpenAlex
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