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Cancer Discov. 2016 Feb;6(2):166-75. doi: 10.1158/2159-8290.CD-15-0402. Epub 2015 Dec 9.

Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer.

Author information

1
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.
2
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
3
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
4
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
5
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
6
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
7
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
8
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
9
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.
10
Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
11
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
12
Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts.
13
The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
14
Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
15
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
16
Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland.
17
Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
18
Memorial Sloan Kettering Cancer Center, New York, New York.
19
Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
20
Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
21
Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. inGenious Targeting Laboratory, Ronkonkoma, New York.
22
Department of Psychiatry, University of Iowa, Iowa City, Iowa.
23
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.
24
Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
25
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.
26
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.
27
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.
28
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.
29
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.

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.

SIGNIFICANCE:

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.

PMID:
26658419
PMCID:
PMC4744563
DOI:
10.1158/2159-8290.CD-15-0402
[Indexed for MEDLINE]
Free PMC Article

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