Kryklyva Valentyna, Pflüger Michael J, Ouchene Hicham, Volleberg-Gorissen Hanneke, Mensenkamp Arjen R, Jonker Marianne A, van de Water Carlijn, Nagtegaal Iris D, Ligtenberg Marjolijn J L, Brosens Lodewijk A A
Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery CCM|CVK, Charité - Universitätsmedizin Berlin, Germany; Department of Pathology, Graduate School of Life Sciences, Utrecht University, Utrecht, The Netherlands.
Mod Pathol. 2025 May;38(5):100709. doi: 10.1016/j.modpat.2025.100709. Epub 2025 Jan 9.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Approximately 10% of affected individuals have an inherited component. Deleterious germline variants increase the lifetime risk for PDAC and are often associated with an elevated risk for extra-pancreatic malignancies. In this study, we aimed to determine the prevalence and impact of germline pathogenic variants (gPVs) in patients with PDAC and extra-pancreatic malignancies. Using tissue samples and longitudinal data from a nationwide pathology database, we identified patients with PDAC and a set of 7 extra-pancreatic malignancies to investigate the presence of gPVs in 25 cancer susceptibility genes with targeted next-generation sequencing. Of 473 patients with PDAC and at least 1 extra-pancreatic malignancy, 75 (16%) had gPVs. These were predominantly in ATM (n = 22), CDKN2A (n = 14), BRCA2 (n = 10), or CHEK2 (n = 10) genes. The combination of PDAC and ovarian carcinoma carried the highest prevalence of gPVs (4 of 10; 40%), followed by PDAC and melanoma (15 of 53; 28%), and PDAC and gastric cancer (2 of 9; 22%). Patients with PDAC and certain extra-pancreatic malignancies carry a higher burden of gPVs than unselected PDAC cohorts. This is a group that very likely benefits from genetic testing because germline status can have important diagnostic and therapeutic implications for affected individuals and their family members.
胰腺导管腺癌（PDAC）是一种致命疾病。约10%的患者有遗传因素。有害的种系变异会增加患PDAC的终生风险，且常与胰腺外恶性肿瘤风险升高相关。在本研究中，我们旨在确定患有PDAC和胰腺外恶性肿瘤患者中种系致病变异（gPVs）的患病率及其影响。利用来自全国病理数据库的组织样本和纵向数据，我们确定了患有PDAC以及一组7种胰腺外恶性肿瘤的患者，通过靶向二代测序研究25个癌症易感基因中gPVs的存在情况。在473例患有PDAC且至少有一种胰腺外恶性肿瘤的患者中，75例（16%）有gPVs。这些变异主要存在于ATM基因（n = 22）、CDKN2A基因（n = 14）、BRCA2基因（n = 10）或CHEK2基因（n = 10）中。PDAC与卵巢癌组合的gPVs患病率最高（10例中有4例；40%），其次是PDAC与黑色素瘤（53例中有15例；28%），以及PDAC与胃癌（9例中有2例；22%）。患有PDAC和某些胰腺外恶性肿瘤的患者比未经过筛选的PDAC队列携带更高负担的gPVs。这是一组极有可能从基因检测中获益的人群，因为种系状态对受影响个体及其家庭成员可能具有重要的诊断和治疗意义。
