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

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, Rachael S. Stolzenberg-SolomonPeter 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, 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, 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 S. Houlston, 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 Butille, Gemma Tell-Marti, Nicholas K. Hayward, Nicholas G. Martin, Grant Montgomery, David L. Duffy, David C. Whiteman, Stuart MacGregor, Donato Calista, Giorgio 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 Molven, 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, Olivier 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 Friedman, 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

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Article number15034
JournalNature communications
Volume8
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
We acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR, NCI), as well as Mr Timothy Myers and Lea Jessop (LTG, DCEG, NCI) for their invaluable help throughout the project. We are grateful to Dr Francisco X. Real, The Spanish National Cancer Institute (CNIO) in Madrid, Spain for providing reagents. We are grateful to Dr Dom Esposito, Frederick National Laboratory for Cancer Research, Frederick, MD, USA, for cloning for lentiviral production. We thank Paul D.P. Pharoah, Department of Oncology, University of Cambridge, Cambridge, UK and Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK for providing GWAS data. Furthermore, we thank Dr Stephen Chanock for his advice, encouragement and critical reading of the manuscript. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute, by contract number HHSN261200800001E, by Cancer Research UK for SEARCH (C490/A10124). Funding for M.V. was provided by the Netherlands Organization for Scientific Research (NWO Gravitation Program Cancer Genomics Netherlands). Funding for M.M. was provided by a grant from the Marie Curie Initial Training Network (ITN) DevCom (FP7, grant number 607142). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Fingerprint Dive into the research topics of 'Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148'. Together they form a unique fingerprint.

Cite this