The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes

• DOI: 10.1007/s10689-017-0019-5
• Publication Date: 2017-07-08T00:57:56Z
• Authors: Thomas P. Slavin; Susan L. Neuhausen; Bita Nehoray; Mariana Niell-Swi...; Ilana Solomon; Christina Rybak; Kathleen Blazer; Aaron Adamson; Kai Yang; Sharon Sand; Nancy Guerrero-Ll...; Danielle Castillo; Josef Herzog; Xiwei Wu; Shu Tao; Shivali Raja; Vincent Chung; Gagandeep Singh; Sue Nadesan; Sandra Brown; Marcia Cruz-Correa; Gloria M. Petersen; Jeffrey Weitzel
• Keywords: Adult; Aged, 80 and over; BRCA2 Protein; Male; 0301 basic medicine; DNA Mutational Analysis; DNA Helicases; High-Throughput Nucleotide Sequencing; Middle Aged; 16. Peace & justice; 3. Good health; Fanconi Anemia Complementation Group F Protein; 03 medical and health sciences; Fanconi Anemia; Neoplastic Syndromes, Hereditary; Mutation; Biomarkers, Tumor; Humans; Female; Genetic Predisposition to Disease; Genetic Testing; Germ-Line Mutation; Aged; Carcinoma, Pancreatic Ductal

Approximately 5-10% of all pancreatic cancer patients carry a predisposing mutation in a known susceptibility gene. Since >90% of patients present with late stage disease, it is crucial to identify high risk individuals who may be amenable to early detection or other prevention. To explore the spectrum of hereditary pancreatic cancer susceptibility, we evaluated germline DNA from pancreatic cancer participants (n = 53) from a large hereditary cancer registry. For those without a known predisposition mutation gene (n = 49), germline next generation sequencing was completed using targeted capture for 706 candidate genes. We identified 16 of 53 participants (30%) with a pathogenic (P) or likely pathogenic (LP) variant that may be related to their hereditary pancreatic cancer predisposition; seven had mutations in genes associated with well-known cancer syndromes (13%) [ATM (2), BRCA2 (3), MSH2 (1), MSH6 (1)]. Many had mutations in Fanconi anemia complex genes [BRCA2 (3 participants), FANCF, FANCM]. Eight participants had rare protein truncating variants of uncertain significance with no other P or LP variants. Earlier age of pancreatic cancer diagnosis (57.5 vs 64.8 years) was indicative of possessing a P or LP variant, as was cancer family history (p values <0.0001). Our multigene panel approach for identifying known cancer predisposing genetic susceptibility in those at risk for hereditary pancreatic cancer may have direct applicability to clinical practice in cases with mutations in actionable genes. Future pancreatic cancer predisposition studies should include evaluation of the Fanconi anemia genes.