Yin Xiaoyi, Shen Hui, Wang Huan, Wang Qingchen, Zhang Shan, Zhang Chunming, Jia Qi, Guo Shiwei, Xu Xiongfei, Zhang Wenhui, Li Bo, Shi Xiaohan, Gao Suizhi, Shi Meilong, Zhao Xuenan, Wang Sheng, Han Jiawei, Zhang Guoxiao, Li Yikai, Li Penghao, Jing Wei, Song Bin, Zheng Kailian, Li Gang, Zhang Yijie, Jiang Hui, Wu Cong, Song Zhijian, Niu Gang, Zhang Qiangzu, Guo Jianglong, Sun Zhen, Han Fengxian, Li Yunguang, Gao Dong, Jin Haojie, Yang Hongbo, Li Jing, Jin Gang
Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200433, China.
Department of Pathology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200433, China.
Nat Commun. 2025 Mar 5;16(1):2214. doi: 10.1038/s41467-025-57520-3.
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.
对高危个体进行胰腺癌（PAAD）筛查可显著降低癌症发病率和死亡率。以往的研究已对PAAD中的体细胞突变进行了分析。相比之下，PAAD易感基因中的突变患病率尚未明确，尤其是在亚洲人群中。我们采用多层队列设计和全基因组/外显子组测序，与11项泛种族研究相比，构建了1123名中国癌症患者PAAD的综合种系突变图谱。对于已知的致病/可能致病的种系变异，中国患者与西方队列相比表现出重叠但不同的种系突变模式，其特点是已知PAAD基因（包括BRCA1、BRCA2、ATM、CDKN2A和CHEK2）的突变率较低，以及中国患者特有的CFTR、RAD51D、FANCA、ERCC2和GNAS突变。在杂合性缺失分析后，CFTR成为首要候选基因。我们采用综合多组学和功能验证范式，发现意义未明的有害变异可能损害CFTR的肿瘤抑制功能，并通过使用患者来源的类器官进行药物筛选来证明其临床相关性。我们的多方面方法不仅加深了对PAAD种系突变人群差异的认识，还揭示了靶向治疗干预的潜在途径。
