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Identification of germline genomic copy number variation in familial pancreatic cancer

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Abstract

Adenocarcinoma of the pancreas is a significant cause of cancer mortality, and up to 10 % of cases appear to be familial. Heritable genomic copy number variants (CNVs) can modulate gene expression and predispose to disease. Here, we identify candidate predisposition genes for familial pancreatic cancer (FPC) by analyzing germline losses or gains present in one or more high-risk patients and absent in a large control group. A total of 120 FPC cases and 1,194 controls were genotyped on the Affymetrix 500K array, and 36 cases and 2,357 controls were genotyped on the Affymetrix 6.0 array. Detection of CNVs was performed by multiple computational algorithms and partially validated by quantitative PCR. We found no significant difference in the germline CNV profiles of cases and controls. A total of 93 non-redundant FPC-specific CNVs (53 losses and 40 gains) were identified in 50 cases, each CNV present in a single individual. FPC-specific CNVs overlapped the coding region of 88 RefSeq genes. Several of these genes have been reported to be differentially expressed and/or affected by copy number alterations in pancreatic adenocarcinoma. Further investigation in high-risk subjects may elucidate the role of one or more of these genes in genetic predisposition to pancreatic cancer.

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Acknowledgments

Sources of funding were from National Institute of Health, Pancreatic Cancer Genetic Epidemiology Consortium (PACGENE) Grant#5R01CA097975-08; Lustgarten Foundation; Princess Margaret Hospital Invest-in-Research Fund; Canadian Institute for Health Research (Graduate Research Award; Vanier Doctoral Award); Canadian Society for Surgical Oncology; American Hepato-Pancreato-Biliary Association; Johnson & Johnson Medical Products/University of Toronto Surgeon Scientist Program Fellowship. We thank the following individuals for their contributions: A. Fiebig, A. Franke and S. Schreiber at POPGEN (University of Kiel, Kiel, Germany) and A. Stewart, R. McPherson and R. Roberts of the University of Ottawa Heart Institute (University of Ottawa, Ottawa, Canada) for generously providing population control microarray data; D. Merico and D. Pinto (The Centre for Applied Genomics, Toronto, Canada) for assistance with data review; G. Bader (University of Toronto, Toronto, Canada) and S. Narod (Women’s College Hospital, Toronto, Canada) for review of the manuscript; H. Rothenmund (Samuel Lunenefeld Research Institute, Toronto, Canada) for her help with patient selection for the study; T. Selander of the Biospecimen Repository (Samuel Lunenfeld Research Institute, Toronto, Canada) for DNA extraction and storage. PACGENE coordinators (Mayo Clinic: J. Cogswell, T. Hammer, C. Wong; JHU: D. Echavarria; Karmanos: K. Sargent; MDA: P. Adatto, G. Armstrong; Dana Farber: M. Lenn, M. Perez, C. Ukaegbu).

Conflict of interest

There are no conflicts of interest to be disclosed by any author of this manuscript.

Ethical approval

All experiments described in this study comply with Canadian and US law and were approved by the appropriate ethics review boards at associated institutions.

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Authors and Affiliations

  1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

    Wigdan Al-Sukhni, Sarah Joe, Nora Zwingerman, George Zogopoulos, Ayelet Borgida, Spring Holter, Aaron Gropper, Sara Moore & Steven Gallinger

  2. Division of General Surgery, Department of Surgery, University of Torontom, Toronto, ON, Canada

    Wigdan Al-Sukhni, George Zogopoulos & Steven Gallinger

  3. Program in Genetics and Genome Biology, The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON, Canada

    Anath C. Lionel, Christian R. Marshall & Stephen W. Scherer

  4. Department of Molecular Genetics, McLaughlin Centre, University of Toronto, Toronto, ON, Canada

    Anath C. Lionel & Stephen W. Scherer

  5. MD Anderson Cancer Center, Houston, TX, USA

    Melissa Bondy

  6. The Sol Goldman Pancreatic Research Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Alison P. Klein

  7. Mayo Clinic College of Medicine, Rochester, MN, USA

    Gloria M. Petersen & Kari G. Rabe

  8. Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Ann G. Schwartz

  9. Dana-Farber Cancer Institute, Boston, MA, USA

    Sapna Syngal

  10. Toronto General Hospital, 10th Floor Rm 10EN206, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada

    Steven Gallinger

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  1. Wigdan Al-Sukhni
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  2. Sarah Joe
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Correspondence to Steven Gallinger.

Electronic supplementary material

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Online Resource 1 Details of FPC cases included in the CNV analysis (XLS 63 kb)

Online Resource 2 Details of controls included in the CNV analysis (XLS 251 kb)

Online Resource 3 Analysis pipeline for Affymetrix 500K SNP microarray data (TIFF 74 kb)

439_2012_1183_MOESM4_ESM.tif

Online Resource 4 Rules for merging CNVs if overlapping between algorithms, chips, and/or samples. If length of overlap between two CNVs equals 20% of length of either CNV (in base pairs), the two CNVs are merged into one CNV (TIFF 52 kb)

439_2012_1183_MOESM5_ESM.xls

Online Resource 5 Detailed list of RefSeq genes whose exons and 5’ & 3’ untranslated regions overlap FPC-specific CNVs (XLS 55 kb)

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Al-Sukhni, W., Joe, S., Lionel, A.C. et al. Identification of germline genomic copy number variation in familial pancreatic cancer. Hum Genet 131, 1481–1494 (2012). https://doi.org/10.1007/s00439-012-1183-1

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