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Research Briefs

Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer

Nicholas J. Roberts, Alexis L. Norris, Gloria M. Petersen, Melissa L. Bondy, Randall Brand, Steven Gallinger, Robert C. Kurtz, Sara H. Olson, Anil K. Rustgi, Ann G. Schwartz, Elena Stoffel, Sapna Syngal, George Zogopoulos, Syed Z. Ali, Jennifer Axilbund, Kari G. Chaffee, Yun-Ching Chen, Michele L. Cote, Erica J. Childs, Christopher Douville, Fernando S. Goes, Joseph M. Herman, Christine Iacobuzio-Donahue, Melissa Kramer, Alvin Makohon-Moore, Richard W. McCombie, K. Wyatt McMahon, Noushin Niknafs, Jennifer Parla, Mehdi Pirooznia, James B. Potash, Andrew D. Rhim, Alyssa L. Smith, Yuxuan Wang, Christopher L. Wolfgang, Laura D. Wood, Peter P. Zandi, Michael Goggins, Rachel Karchin, James R. Eshleman, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Ralph H. Hruban and Alison P. Klein
Nicholas J. Roberts
1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
2Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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  • For correspondence: vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu
Alexis L. Norris
1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Gloria M. Petersen
3Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
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Melissa L. Bondy
4Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
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Randall Brand
5Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Steven Gallinger
6Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
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Robert C. Kurtz
7Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Sara H. Olson
8Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Anil K. Rustgi
9Division 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.
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Ann G. Schwartz
10Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
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Elena Stoffel
11Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Sapna Syngal
12Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts.
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George Zogopoulos
13The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
14Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
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Syed Z. Ali
1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Jennifer Axilbund
1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Kari G. Chaffee
3Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
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Yun-Ching Chen
15Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
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Michele L. Cote
10Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
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Erica J. Childs
16Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
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Christopher Douville
15Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
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Fernando S. Goes
17Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Joseph M. Herman
18Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Christine Iacobuzio-Donahue
19Memorial Sloan Kettering Cancer Center, New York, New York.
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Melissa Kramer
20Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
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Alvin Makohon-Moore
1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Richard W. McCombie
20Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
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K. Wyatt McMahon
2Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Noushin Niknafs
15Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
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Jennifer Parla
20Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
21inGenious Targeting Laboratory, Ronkonkoma, New York.
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Mehdi Pirooznia
17Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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James B. Potash
22Department of Psychiatry, University of Iowa, Iowa City, Iowa.
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Andrew D. Rhim
9Division 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.
23Department of Medicine, University of Michigan, Ann Arbor, Michigan.
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Alyssa L. Smith
13The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
14Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
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Yuxuan Wang
2Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Christopher L. Wolfgang
24Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Laura D. Wood
1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
18Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Peter P. Zandi
17Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Michael Goggins
1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
18Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
25Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Rachel Karchin
15Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
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James R. Eshleman
1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
18Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Nickolas Papadopoulos
2Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Kenneth W. Kinzler
2Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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  • For correspondence: vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu
Bert Vogelstein
2Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Ralph H. Hruban
1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
18Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Alison P. Klein
1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
16Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
18Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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  • For correspondence: vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu
DOI: 10.1158/2159-8290.CD-15-0402 Published February 2016
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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. Cancer Discov; 6(2); 166–75. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 109

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received April 3, 2015.
  • Revision received November 25, 2015.
  • Accepted December 2, 2015.
  • ©2015 American Association for Cancer Research.
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Cancer Discovery: 6 (2)
February 2016
Volume 6, Issue 2
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Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer
Nicholas J. Roberts, Alexis L. Norris, Gloria M. Petersen, Melissa L. Bondy, Randall Brand, Steven Gallinger, Robert C. Kurtz, Sara H. Olson, Anil K. Rustgi, Ann G. Schwartz, Elena Stoffel, Sapna Syngal, George Zogopoulos, Syed Z. Ali, Jennifer Axilbund, Kari G. Chaffee, Yun-Ching Chen, Michele L. Cote, Erica J. Childs, Christopher Douville, Fernando S. Goes, Joseph M. Herman, Christine Iacobuzio-Donahue, Melissa Kramer, Alvin Makohon-Moore, Richard W. McCombie, K. Wyatt McMahon, Noushin Niknafs, Jennifer Parla, Mehdi Pirooznia, James B. Potash, Andrew D. Rhim, Alyssa L. Smith, Yuxuan Wang, Christopher L. Wolfgang, Laura D. Wood, Peter P. Zandi, Michael Goggins, Rachel Karchin, James R. Eshleman, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Ralph H. Hruban and Alison P. Klein
Cancer Discov February 1 2016 (6) (2) 166-175; DOI: 10.1158/2159-8290.CD-15-0402

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Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer
Nicholas J. Roberts, Alexis L. Norris, Gloria M. Petersen, Melissa L. Bondy, Randall Brand, Steven Gallinger, Robert C. Kurtz, Sara H. Olson, Anil K. Rustgi, Ann G. Schwartz, Elena Stoffel, Sapna Syngal, George Zogopoulos, Syed Z. Ali, Jennifer Axilbund, Kari G. Chaffee, Yun-Ching Chen, Michele L. Cote, Erica J. Childs, Christopher Douville, Fernando S. Goes, Joseph M. Herman, Christine Iacobuzio-Donahue, Melissa Kramer, Alvin Makohon-Moore, Richard W. McCombie, K. Wyatt McMahon, Noushin Niknafs, Jennifer Parla, Mehdi Pirooznia, James B. Potash, Andrew D. Rhim, Alyssa L. Smith, Yuxuan Wang, Christopher L. Wolfgang, Laura D. Wood, Peter P. Zandi, Michael Goggins, Rachel Karchin, James R. Eshleman, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Ralph H. Hruban and Alison P. Klein
Cancer Discov February 1 2016 (6) (2) 166-175; DOI: 10.1158/2159-8290.CD-15-0402
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