Dokument

Summary:
Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer related death in Germany by 2030. Despite extensive research in recent years, PDAC still has a dismal prognosis. About 5-10% of PDAC cases accumulate in families, due to the familial pancreatic cancer syndrome, other hereditary cancer syndromes or hereditary pancreatic dysfunctionality syndromes. Families with at least two first-degree relatives affected with PDAC without fulfilling the criteria of other cancer syndromes are defined as familial pancreatic cancer (FPC). So far BRCA1, BRCA2, CDKN2A, PALB2, CHEK2 have been identified as susceptibility genes for FPC, but predisposing germline mutations in these genes have been identified in only about 10% of FPC families. Previously, it was hypothesized that the Ataxia telangiectasia mutated (ATM) gene might also be a low penetrance FPC susceptibility gene. Therefore, we analysed 35 FPC families of the National Case Collection for familial pancreatic cancer (FaPaCa) registry by Whole Genome Sequencing, Sanger Sequencing and Multiplex ligation-dependent probe amplification (MLPA) to determine the role of ATM in FPC. A deleterious ATM germline mutation (X175Y) was detected 1 of these 35 FPC families according to a prevalence of 2.9%. Deleteriousness of the mutation tested positively using MutationTaster, PolyPhen2, SIFT and PROVEAN. ATM can be considered as a low penetrance FPC susceptibility gene, which might also predispose to other cancers despite PDAC. Further studies are needed to clarify whether there might be a genotype/phenotype correlation.

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