title: BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.
abstract: OBJECTIVE
  Familial pancreatic cancer kindreds contain at least two affected first-degree relatives. Comprehensive data are needed to assist clinical risk assessment and genetic testing.
  
  
  METHODS
  Germ-line DNA samples from 727 unrelated probands with positive family history (521 met criteria for familial pancreatic cancer) were tested in compliance with the Clinical Laboratory Improvement Amendments for mutations in BRCA1 and BRCA2 (including analysis of deletions and rearrangements), PALB2, and CDKN2A. We compared prevalence of deleterious mutations between familial pancreatic cancer probands and nonfamilial pancreatic cancer probands (kindreds containing at least two affected biological relatives, but not first-degree relatives). We also examined the impact of family history on breast and ovarian cancers and melanoma.
  
  
  RESULTS
  Prevalence of deleterious mutations (excluding variants of unknown significance) among familial pancreatic cancer probands was: BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. Familial pancreatic cancer probands carry more mutations in the four genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%) (odds ratio: 2.40; 95% confidence interval: 1.06-5.44; P = 0.03). The probability of testing positive for deleterious mutations in any of the four genes ranges up to 10.4%, depending on family history of cancers. BRCA2 and CDKN2A account for the majority of mutations in familial pancreatic cancer.
  
  
  CONCLUSIONS
  Genetic testing of multiple relevant genes in probands with a positive family history is warranted, particularly for familial pancreatic cancer.
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Zhen
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Kari G
authors.initials: KG
authors.lastname: Rabe
authors.affiliation: Divison of General Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
authors.affiliation: Department of Oncology, Karmanos Cancer Institute and Wayne State University, Detroit, Michigan, USA.
authors.forename: Ann G
authors.initials: AG
authors.lastname: Schwartz
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Goggins
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Department of Oncology, Karmanos Cancer Institute and Wayne State University, Detroit, Michigan, USA.
authors.forename: Michele L
authors.initials: ML
authors.lastname: Cote
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
authors.affiliation: 1] The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA [2] Ludwig Center for Cancer Genetics, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Roberts
authors.affiliation: Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cannon-Albright
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Donghui
authors.initials: D
authors.lastname: Li
authors.affiliation: Myriad Genetic Laboratories, Inc., Salt Lake City, Utah, USA.
authors.forename: Kelsey
authors.identifier: 0000000326023668
authors.initials: K
authors.lastname: Moyes
authors.affiliation: Myriad Genetic Laboratories, Inc., Salt Lake City, Utah, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wenstrup
authors.affiliation: Myriad Genetic Laboratories, Inc., Salt Lake City, Utah, USA.
authors.forename: Anne-Renee
authors.initials: AR
authors.lastname: Hartman
authors.affiliation: Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Seminara
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Alison P
authors.initials: AP
authors.lastname: Klein
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D024682:BRCA2 Protein / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases