title: Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.
abstract: OBJECTIVE
  We investigated the prevalence of germline mutations in APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53 in patients with pancreatic cancer.
  
  
  METHODS
  The Ontario Pancreas Cancer Study enrolls consenting participants with pancreatic cancer from a province-wide electronic pathology database; 708 probands were enrolled from April 2003 through August 2012. To improve the precision of BRCA2 prevalence estimates, 290 probands were selected from 3 strata, based on family history of breast and/or ovarian cancer, pancreatic cancer, or neither. Germline DNA was analyzed by next-generation sequencing using a custom multiple-gene panel. Mutation prevalence estimates were calculated from the sample for the entire cohort.
  
  
  RESULTS
  Eleven pathogenic mutations were identified: 3 in ATM, 1 in BRCA1, 2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53. The prevalence of mutations in all 13 genes was 3.8% (95% confidence interval, 2.1%-5.6%). Carrier status was associated significantly with breast cancer in the proband or first-degree relative (P < .01), and with colorectal cancer in the proband or first-degree relative (P < .01), but not family history of pancreatic cancer, age at diagnosis, or stage at diagnosis. Of patients with a personal or family history of breast and colorectal cancer, 10.7% (95% confidence interval, 4.4%-17.0%) and 11.1% (95% confidence interval, 3.0%-19.1%) carried pathogenic mutations, respectively.
  
  
  CONCLUSIONS
  A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes. The heterogeneity of mutations identified in this study shows the value of using a multiple-gene panel in pancreatic cancer.
authors.affiliation: Ontario Institute for Cancer Research, Canada; Department of Medicine, University of Toronto, Canada.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Grant
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada.
authors.forename: Iris
authors.initials: I
authors.lastname: Selander
authors.affiliation: Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Canada.
authors.forename: Ashton A
authors.initials: AA
authors.lastname: Connor
authors.affiliation: Laboratory Medicine and Pathobiology, University of Toronto, Canada.
authors.forename: Shamini
authors.initials: S
authors.lastname: Selvarajah
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Borgida
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Briollais
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.affiliation: Ontario Institute for Cancer Research, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Canada; Pathology and Laboratory Medicine, Mount Sinai Hospital, Canada.
authors.forename: Jordan
authors.initials: J
authors.lastname: Lerner-Ellis
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada.
authors.forename: Spring
authors.initials: S
authors.lastname: Holter
authors.affiliation: Ontario Institute for Cancer Research, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada; Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Canada. Electronic address: steven.gallinger@uhn.on.ca.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
mesh_terms: D004931:Esophageal Achalasia / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics*; D006519:Hepatitis, Alcoholic / Q000276:immunology*; D006801:Humans; D016031:Liver Transplantation / Q000639:trends*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D065626:Non-alcoholic Fatty Liver Disease / Q000453:epidemiology*; D010190:Pancreatic Neoplasms / Q000235:genetics*
chemical_list: C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I
keywords: Cancer Risk; Familial Pancreatic Cancer; Pancreatic Cancer Genetics