title: Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer.
abstract: Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types.
  
  
  CONCLUSIONS
  The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer.
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Roberts
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Alexis L
authors.initials: AL
authors.lastname: Norris
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Bondy
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Randall
authors.initials: R
authors.lastname: Brand
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kurtz
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sara H
authors.initials: SH
authors.lastname: Olson
authors.affiliation: Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Ann G
authors.initials: AG
authors.lastname: Schwartz
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Elena
authors.initials: E
authors.lastname: Stoffel
authors.affiliation: Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
authors.affiliation: The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Zogopoulos
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Syed Z
authors.initials: SZ
authors.lastname: Ali
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Axilbund
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Kari G
authors.initials: KG
authors.lastname: Chaffee
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Yun-Ching
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Michele L
authors.initials: ML
authors.lastname: Cote
authors.affiliation: Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Childs
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Douville
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Fernando S
authors.initials: FS
authors.lastname: Goes
authors.affiliation: Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Herman
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donahue
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors.forename: Melissa
authors.initials: M
authors.lastname: Kramer
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Alvin
authors.initials: A
authors.lastname: Makohon-Moore
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors.forename: Richard W
authors.initials: RW
authors.lastname: McCombie
authors.affiliation: Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: K Wyatt
authors.initials: KW
authors.lastname: McMahon
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Noushin
authors.initials: N
authors.lastname: Niknafs
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. inGenious Targeting Laboratory, Ronkonkoma, New York.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Parla
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Pirooznia
authors.affiliation: Department of Psychiatry, University of Iowa, Iowa City, Iowa.
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
authors.affiliation: Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rhim
authors.affiliation: The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Alyssa L
authors.initials: AL
authors.lastname: Smith
authors.affiliation: Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Zandi
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Goggins
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
authors.affiliation: Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu.
authors.forename: Alison P
authors.initials: AP
authors.lastname: Klein
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D002277:Carcinoma / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics*; D017354:Point Mutation; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins