IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v8y2017i1d10.1038_ncomms15034.html
   My bibliography  Save this article

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Author

Listed:
  • Jun Fang

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Jinping Jia

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Matthew Makowski

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
    Radboud Institute for Molecular Life Sciences, Radboud University)

  • Mai Xu

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Zhaoming Wang

    (National Cancer Institute, National Institutes of Health
    Cancer Genomics Research Laboratory, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research)

  • Tongwu Zhang

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Jason W. Hoskins

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Jiyeon Choi

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Younghun Han

    (Geisel School of Medicine, Dartmouth College)

  • Mingfeng Zhang

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Janelle Thomas

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Michael Kovacs

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Irene Collins

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Marta Dzyadyk

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Abbey Thompson

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Maura O'Neill

    (Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research)

  • Sudipto Das

    (Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research)

  • Qi Lan

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Roelof Koster

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Rachael S. Stolzenberg-Solomon

    (National Cancer Institute, National Institutes of Health)

  • Peter Kraft

    (Harvard School of Public Health
    Harvard School of Public Health)

  • Brian M. Wolpin

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital and Harvard Medical School)

  • Pascal W. T. C. Jansen

    (Radboud Institute for Molecular Life Sciences, Radboud University)

  • Sara Olson

    (Memorial Sloan-Kettering Cancer Center)

  • Katherine A. McGlynn

    (National Cancer Institute, National Institutes of Health)

  • Peter A. Kanetsky

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Nilanjan Chatterjee

    (National Cancer Institute, National Institutes of Health)

  • Jennifer H. Barrett

    (Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds)

  • Alison M. Dunning

    (University of Cambridge)

  • John C. Taylor

    (Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds)

  • Julia A. Newton-Bishop

    (Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds)

  • D. Timothy Bishop

    (Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds)

  • Thorkell Andresson

    (Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research)

  • Gloria M. Petersen

    (Mayo Clinic)

  • Christopher I. Amos

    (Geisel School of Medicine, Dartmouth College)

  • Mark M. Iles

    (Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds)

  • Katherine L. Nathanson

    (Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania)

  • Maria Teresa Landi

    (National Cancer Institute, National Institutes of Health)

  • Michiel Vermeulen

    (Radboud Institute for Molecular Life Sciences, Radboud University)

  • Kevin M. Brown

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

  • Laufey T. Amundadottir

    (Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health)

Abstract

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.

Suggested Citation

  • Jun Fang & Jinping Jia & Matthew Makowski & Mai Xu & Zhaoming Wang & Tongwu Zhang & Jason W. Hoskins & Jiyeon Choi & Younghun Han & Mingfeng Zhang & Janelle Thomas & Michael Kovacs & Irene Collins & M, 2017. "Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148," Nature Communications, Nature, vol. 8(1), pages 1-17, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15034
    DOI: 10.1038/ncomms15034
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms15034
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms15034?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15034. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.