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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-05-02

AUTHORS

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, Marta Dzyadyk, Abbey Thompson, Maura O'Neill, Sudipto Das, Qi Lan, Roelof Koster, PanScan Consortium, Federico Canzian, Charles Kooperberg, Alan A Arslan, Paige M Bracci, Julie Buring, Eric J Duell, Steven Gallinger, Eric J Jacobs, Aruna Kamineni, Stephen Van Den Eeden, Alison P Klein, Laurence N Kolonel, Donghui Li, Sara H Olson, Harvey A Risch, Howard D Sesso, Kala Visvanathan, Wei Zheng, Demetrius Albanes, Melissa A Austin, Marie-Christine Boutron-Ruault, H Bas Bueno-de-Mesquita, Michelle Cotterchio, J Michael Gaziano, Edward L Giovannucci, Michael Goggins, Myron Gross, Manal Hassan, Kathy J Helzlsouer, Elizabeth A Holly, David J Hunter, Mazda Jenab, Rudolf Kaaks, Timothy J Key, Kay-Tee Khaw, Vittorio Krogh, Robert C Kurtz, Andrea LaCroix, Loic Le Marchand, Satu Mannisto, Alpa V Patel, Petra H M Peeters, Elio Riboli, Xiao-Ou Shu, Malin Sund, Mark Thornquist, Anne Tjønneland, Geoffrey S Tobias, Dimitrios Trichopoulos, Jean Wactawski-Wende, Herbert Yu, Kai Yu, Anne Zeleniuch-Jacquotte, Robert Hoover, Patricia Hartge, Charles Fuchs, Stephen J Chanock, TRICL Consortium, Victoria Stevens, Demetrios Albanes, Neil E Caporaso, Paul Brennan, James McKay, Xifeng Wu, Rayjean J Hung, John R McLaughlin, Heike Bickeboller, Angela Risch, Erich Wichmann, Richard Houlston, GenoMEL Consortium, Graham Mann, John Hopper, Joanne Aitken, Bruce Armstrong, Graham Giles, Elizabeth Holland, Richard Kefford, Anne Cust, Mark Jenkins, Helen Schmid, Susana Puig, Paula Aguilera, Celia Badenas, Alicia Barreiro, Cristina Carrera, Daniel Gabriel, Pol Gimenez-Xavier, Pablo Iglesias-Garcia, Josep Malvehy, Montse Mila, Ramon Pigem, Miriam Potrony, Joan Anton Puig-Batille, Gemma Tell-Marti, Nicholas K. Hayward, Nicholas G. Martin, Grant Montgomery, David L. Duffy, David C. Whiteman, Stuart MacGregor, Donato Calista, Giorgi Landi, Paola Minghetti, Fabio Arcangeli, Pier Alberto Bertazzi, Paola Ghiorzo, Giovanna Bianchi-Scarra, Lorenze Pastorino, William Bruno, Virginia Andreotti, Paola Queirolo, Francesco Spagnolo, Rona MacKie, Julie Lang, Nelleke Gruis, Frans A van Nieuwpoort, Coby Out, Wilma Bergman, Nicole Kukutsch, Jan Nico Bouwes Bavinck, Bert Bakker, Nienke van der Stoep, Jeanet ter Huurne, Han van der Rhee, Marcel Bekkenk, Dyon Snels, Marinus van Praag, Lieve Brochez, Rianne Gerritsen, Marianne Crijns, Hans Vasen, Bart Janssen, Christian Ingvar, Håkan Olsson, Göran Jönsson, Åke Borg, Katja Harbst, Kari Nielsen, Anita Schmidt Zander, Anders Molvern, Per Helsing, Per Arne Andresen, Helge Rootwelt, Lars A Akslen, Brigitte Bressac-de Paillerets, Florence Demenais, Marie-Francoise Avril, Valerie Chaudru, Patricia Jeannin, Fabienne Lesueur, Eve Maubec, Hamida Mohamdi, Myriam Bossard, Amaury Vaysse, Francoise Boitier, Oliver Caron, Frederic Caux, Stephane Dalle, Olivier Dereure, Dominique Leroux, Ludovic Martin, Christine Mateus, Caroline Robert, Dominique Stoppa-Lyonnet, Luc Thomas, Eva Wierzbicka, David E. Elder, Michael Ming, Nandita Mitra, Tadeusz Debniak, Jan Lubinski, Marko Hocevar, Srdjan Novakovic, Barbara Peric, Petra Skerl, Johan Hansson, Veronica Höiom, Eitan Freidman, Esther Azizi, Orna Baron-Epel, Alon Scope, Felix Pavlotsky, Irit Cohen-Manheim, Yael Laitman, Mark Harland, Juliette Randerson-Moor, Jon Laye, John Davies, Jeremie Nsengimana, Sally O'Shea, May Chan, Jo Gascoyne, Margaret A Tucker, Alisa M Goldstein, Xiaohong R Yang, Rachael S. Stolzenberg-Solomon, Peter Kraft, Brian M. Wolpin, Pascal W. T. C. Jansen, Sara Olson, Katherine A. McGlynn, Peter A. Kanetsky, Nilanjan Chatterjee, Jennifer H. Barrett, Alison M. Dunning, John C. Taylor, Julia A. Newton-Bishop, D. Timothy Bishop, Thorkell Andresson, Gloria M. Petersen, Christopher I. Amos, Mark M. Iles, Katherine L. Nathanson, Maria Teresa Landi, Michiel Vermeulen, Kevin M. Brown, Laufey T. Amundadottir

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. More... »

PAGES

15034

References to SciGraph publications

Journal

TITLE

Nature Communications

ISSUE

N/A

VOLUME

8

Author Affiliations

  • National Institutes of Health
  • Radboud University Nijmegen
  • Frederick National Laboratory for Cancer Research
  • Dartmouth College
  • German Cancer Research Center
  • Fred Hutchinson Cancer Research Center
  • New York University
  • University of California, San Francisco
  • Harvard University
  • Lunenfeld-Tanenbaum Research Institute
  • American Cancer Society
  • Group Health Cooperative
  • Johns Hopkins University
  • University of Hawaii at Manoa
  • The University of Texas MD Anderson Cancer Center
  • Memorial Sloan Kettering Cancer Center
  • Yale University
  • Vanderbilt University Medical Center
  • University of Washington
  • Institut Gustave Roussy
  • Imperial College London
  • University of Toronto
  • University of Minnesota
  • Mercy Medical Center
  • International Agency For Research On Cancer
  • University of Oxford
  • University of Cambridge
  • Istituto Nazionale dei Tumori
  • National Institute for Health and Welfare
  • Umeå University
  • Danish Cancer Society
  • Hellenic Health Foundation
  • University at Buffalo, State University of New York
  • Dana–Farber Cancer Institute
  • University of Salzburg
  • Helmholtz Zentrum München
  • Institute of Cancer Research
  • Melanoma Institute Australia
  • Westmead Institute for Medical Research
  • University of Melbourne
  • Cancer Council Queensland
  • University of Sydney
  • Cancer Council Victoria
  • Macquarie University
  • University of Barcelona
  • Hospital Clinic of Barcelona
  • QIMR Berghofer Medical Research Institute
  • University of Queensland
  • Ospedale Maurizio Bufalini
  • University of Milan
  • Ospedale San Martino
  • University of Glasgow
  • Leiden University Medical Center
  • Academic Medical Center
  • Sint Franciscus Gasthuis
  • Ghent University Hospital
  • Radboud University Nijmegen Medical Centre
  • Lund University
  • University of Bergen
  • Haukeland University Hospital
  • Oslo University Hospital
  • Hôpital Cochin
  • Paris Descartes University
  • University of Évry Val d'Essonne
  • Hôpital Avicenne
  • Hospices Civils de Lyon
  • Institute Curie
  • Centre Hospitalier Universitaire de Angers
  • Centre Hospitalier Universitaire de Poitiers
  • University of Poitiers
  • University of Pennsylvania
  • Pomeranian Medical University
  • Institute of Oncology Ljubljana
  • Sheba Medical Center
  • Tel Aviv University
  • University of Haifa
  • Hebrew University of Jerusalem
  • University of Leeds
  • Brigham and Women's Hospital
  • Moffitt Cancer Center
  • Mayo Clinic
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ncomms15034

    DOI

    http://dx.doi.org/10.1038/ncomms15034

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1085075484

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28447668


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