Familial pancreatic cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 could be detected in 10-15% of analyzed families. Thus, the genetic basis of disease susceptibility in the majority of FPC families remains unknown. In an attempt to identify new candidate genes, we performed whole-genome sequencing on affected patients from 15 FPC families, without detecting BRCA1/2, CDKN2A or PALB2 mutations, using an Illumina based platform. Annotations from CADD, PolyPhen-2, SIFT, Mutation Taster and PROVEAN were used to assess the potential impact of a variant on the function of a gene. Variants that did not segregate with pancreatic disease in respective families were excluded. Potential predisposing candidate genes ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 were identified in 7 of 15 families. All identified gene mutations segregated with pancreatic disease, but sometimes with incomplete penetrance. An analysis of up to 46 additional FPC families revealed that the identified gene mutations appeared to be unique in most cases, despite a potentially deleterious ACAD9 Ala326Thr germline variant, which occurred in 4 (8.7%) of 46 FPC families. Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants.

Bioinformatics and Omics Data Analytics German Cancer Research Center D 69120 Heidelberg Germany

Biomedical Center Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague 30605 Pilsen Czech Republic

Biomedical Informatics Data Mining and Data Analytics Augsburg University D 86159 Augsburg Germany

Chair of Genetic Epidemiology IBE Faculty of Medicine LMU Munich D 81377 Munich Germany

Computational Oncology Molecular Diagnostics Program National Center for Tumor Diseases D 69120 Heidelberg Germany

Department of Visceral Thoracic and Vascular Surgery Philipps University D 35043 Marburg Germany

German Cancer Research Center D 69120 Heidelberg Germany

German Cancer Research Center Division of Cancer Epidemiology D 69120 Heidelberg Germany

German Cancer Research Center Division of Molecular Genetic Epidemiology D 69120 Heidelberg Germany

Helmholtz Zentrum München German Research Center for Environmental Health Institute of Genetic Epidemiology D 85764 Neuherberg Germany

Hopp Children's Cancer Center D 69120 Heidelberg Germany

Institute of Medical Biometry Epidemiology and Informatics University Medical Center Johannes Gutenberg University D 55101 Mainz Germany

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