title: Identification of germline genetic mutations in patients with pancreatic cancer.
abstract: BACKGROUND
  Pancreatic adenocarcinoma (PAC) is part of several cancer predisposition syndromes; however, indications for genetic counseling/testing are not well-defined. In the current study, the authors sought to determine mutation prevalence and characteristics that are predictive of an inherited predisposition for PAC.
  
  
  METHODS
  A total of 175 consecutive patients with PAC who underwent clinical genetics assessment at Memorial Sloan Kettering Cancer Center between 2011 and 2014 were identified. Clinical data, family history, and germline results were evaluated.
  
  
  RESULTS
  Among 159 patients with PAC who pursued genetic testing, 24 pathogenic mutations were identified (15.1%; 95% confidence interval, 9.5%-20.7%), including BRCA2 (13 mutations), BRCA1 (4 mutations), p16 (2 mutations), PALB2 (1 mutation), and Lynch syndrome (4 mutations). BRCA1/BRCA2 prevalence was 13.7% in Ashkenazi Jewish (AJ) patients (95 patients) and 7.1% in non-AJ patients (56 patients). In AJ patients with a strong, weak, or absent family history of BRCA-associated cancers, the mutation prevalence was 16.7%, 15.8%, and 7.4%, respectively. The mean age at the time of diagnosis in all mutation carriers was 58.5 years (range, 45-75 years) compared with 64 years (range, 27-87 years) in those not carrying a mutation (P = .02). Although BRCA2 was the most common mutation identified, no patients with early-onset PAC (diagnosed at age ≤ 50 years) harbored a BRCA2 mutation and the mean age at diagnosis in BRCA2 carriers was equivalent to that of individuals who were not mutation carriers (P = .34). Mutation prevalence in patients with early-onset disease (21 patients) was 28.6%, including BRCA1 (2 mutations), p16 (2 mutations), MSH2 (1 mutation), and MLH1 (1 mutation).
  
  
  CONCLUSIONS
  Mutations in BRCA2 account for > 50% of patients with PAC with an identified susceptibility syndrome. AJ patients were found to have high BRCA1/BRCA2 prevalence regardless of personal/family history, suggesting that ancestry alone indicates a need for genetic evaluation. With the exception of BRCA2-associated PAC, an inherited predisposition for PAC is associated with an earlier age at PAC diagnosis, suggesting that this subset of patients may also represent a population warranting further evaluation.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Salo-Mullen
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: O'Reilly
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsen
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Asad M
authors.initials: AM
authors.lastname: Ashraf
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Maeve A
authors.initials: MA
authors.lastname: Lowery
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Yu
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Reidy
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Epstein
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Anne
authors.initials: A
authors.lastname: Lincoln
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Amethyst
authors.initials: A
authors.lastname: Saldia
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Jacobs
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Rohini
authors.initials: R
authors.lastname: Rau-Murthy
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kurtz
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Leonard
authors.initials: L
authors.lastname: Saltz
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Robson
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Zsofia K
authors.initials: ZK
authors.lastname: Stadler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000230:Adenocarcinoma / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D019942:Genes, p16; D018095:Germ-Line Mutation; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000235:genetics; D006801:Humans; D007585:Jews / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D000076164:Fanconi Anemia Complementation Group N Protein; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
keywords: Ashkenazi Jewish; BRCA; Lynch syndrome; PALB2; genetics; germline; hereditary; mutations; p16; pancreatic cancer