(1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34-0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.

Cancer Research Institute Ghent 9000 Ghent Belgium

Center for Medical Genetics Ghent University and Ghent University Hospital 9000 Ghent Belgium

Center of Medical Genetics UZA UA Antwerp University Hospital 2000 Antwerp Belgium

Department of Clinical Genetics Maastricht University Medical Centre 6229 GR Maastricht The Netherlands

Department of Gastroenterology Ghent University Hospital 9000 Ghent Belgium

Department of Oncology 1st Faculty of Medicine Charles University and General University Hospital Prague 128 00 Prague Czech Republic

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague 128 00 Prague Czech Republic

Digestive Oncology Unit University Hospital Gasthuisberg 3000 Leuven Belgium

GROW School for Oncology and Developmental Biology Maastricht University Medical Centre 6200 MD Maastricht The Netherlands

Institute of Biochemistry and Experimental Oncology 1st Faculty of Medicine Charles University 128 53 Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital Prague 128 00 Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague 128 00 Prague Czech Republic

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