Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer.

Emily P Slater,Nagarajan Paramasivam,Kari Hemminki,Lutz Benedikt Böhm,Konstantin Strauch,Elvira Matthäi,Asta Försti,Manuel Lutz,Norman Gercke,Lisa M Wilke,Matthias Schlesner,Detlef K Bartsch

doi:10.3390/jpm11070631

Abstract

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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in Germany by 2030 [1]
The low-frequency or rare gene variants were identified in the ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 genes
In this study, we identified an ACAD9 variant (Ala326Thr) that was detected in every affected individual with pancreatic ductal adenocarcinoma (PDAC) or its precursor lesions in 4 of 46 (8.7%) familial pancreatic cancer (FPC) families that were characterized by the absence of breast cancer in the pedigree

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in Germany by 2030 [1]. A familial aggregation of PDAC, so-called familial pancreatic cancer (FPC), has been well-established in about 5–10% of cases [2]. FPC describes families with at least two first-degree relatives with PDAC that do not fulfill the criteria for another inherited tumor syndrome [3,4]. The identification of disease-causing genes is important to determine the genetic risk for the development of PDAC in an individual from an FPC family since carriers of deleterious germline mutations profit more from early screening, as they have a higher risk compared to individuals from

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