title: ATM mutations in patients with hereditary pancreatic cancer.
abstract: Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition.
  
  
  CONCLUSIONS
  The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes.
authors.affiliation: Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Roberts
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Jiao
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Bondy
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Ann G
authors.initials: AG
authors.lastname: Schwartz
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
authors.forename: Michele L
authors.initials: ML
authors.lastname: Cote
authors.forename: Jennifer
authors.initials: J
authors.lastname: Axilbund
authors.forename: Richard
authors.initials: R
authors.lastname: Schulick
authors.forename: Syed Z
authors.initials: SZ
authors.lastname: Ali
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Michael
authors.initials: M
authors.lastname: Goggins
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Alison P
authors.initials: AP
authors.lastname: Klein
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases