TY - JOUR
T1 - Germline Pathogenic Variants in Patients with Pancreatic Ductal Adenocarcinoma and Extra-pancreatic Malignancies
T2 - A Nationwide Database Analysis
AU - Kryklyva, Valentyna
AU - Pflüger, Michael J
AU - Ouchene, Hicham
AU - Volleberg-Gorissen, Hanneke
AU - Mensenkamp, Arjen R
AU - Jonker, Marianne A
AU - van de Water, Carlijn
AU - Nagtegaal, Iris D
AU - Ligtenberg, Marjolijn J L
AU - Brosens, Lodewijk A A
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2025/5
Y1 - 2025/5
N2 - 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.
AB - 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.
KW - PDAC
KW - germline pathogenic variants
KW - hereditary pancreatic cancer
KW - next-generation sequencing
KW - wild-type KRAS
UR - https://www.scopus.com/pages/publications/85216568739
U2 - 10.1016/j.modpat.2025.100709
DO - 10.1016/j.modpat.2025.100709
M3 - Article
C2 - 39793706
SN - 0893-3952
VL - 38
JO - Modern Pathology
JF - Modern Pathology
IS - 5
M1 - 100709
ER -