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

2017; Nature Portfolio; Volume: 8; Issue: 1 Linguagem: Inglês

10.1038/ncomms15034

2041-1723

Jun Fang, Jinping Jia, Matthew Makowski, Mai Xu, Zhaoming Wang, Tongwu Zhang, Jason W. Hoskins, Jiyeon Choi, Younghun Han, Mingfeng Zhang, Janelle Thomas, Michael A. Kovacs, Irene Collins, Marta Dzyadyk, Abbey Thompson, Maura O’Neill, Sudipto Das, Qi Lan, Roelof Koster, Federico Canzian, Charles Kooperberg, Zhaoming Wang, Alan A. Arslan, Paige M. Bracci, Julie E. 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 D. Gross, Manal M. 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 Z. LaCroix, Loı̈c Le Marchand, Satu Männistö, Alpa V. Patel, Petra H. Peeters, Elio Ríboli, 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 N. Hoover, Patricia Hartge, Charles S. Fuchs, Stephen J. Chanock, Victoria L. Stevens, Demetrius Albanes, Neil E. Caporaso, Paul Brennan, James McKay, Xifeng Wu, Rayjean J. Hung, Esther M. John, Heike Bickeböller, Angela Risch, Erich Wichmann, Richard S. Houlston, Graham J. Mann, John L. Hopper, Joanne F. Aitken, Bruce K. Armstrong, Graham G. Giles, Elizabeth A. Holland, Richard Kefford, Anne Ε. Cust, Mark A. Jenkins, Helen Schmid, Susana Puig, Paula Aguilera, Célia Bádenas, Alicia Barreiro, Cristina Carrera, Daniel Gabriel, Pol Giménez‐Xavier, Pablo Iglesias-García, Josep Malvehy, Montserrat Milà, Ramón Pigem, Míriam Potrony, Joan Anton Puig-Batille, Gemma Tell‐Martí, Nicholas K. Hayward, Nicholas G. Martin, Grant W. Montgomery, David L. Duffy, David C. Whiteman, Stuart MacGregor, Donato Calista, Giorgi Landi, Paola Minghetti, Fabio Arcangeli, Pier Alberto Bertazzi, Paola Ghiorzo, Giovanna Bianchi‐Scarrà, Lorenza Pastorino, William Bruno, Virginia Andreotti, Paola Queirolo, Francesco Spagnolo, Rona M. MacKie, Julie Lang, Nelleke A. Gruis, Frans A. van Nieuwpoort, Coby Out, Wilma Bergman, Nicole A. Kukutsch, Jan Nico Bouwes Bavinck, Egbert Bakker, Nienke van der Stoep, Jeanet ter Huurne, Han van der Rhee, Marcel W. Bekkenk, Dyon Snels, Marinus van Praag, Liève Brochez, Rianne M. J. P. Gerritsen, Marianne B. Crijns, Hans F. A. Vasen, Bart Janssen, Christian Ingvar, Håkan Olsson, Göran Jönsson, Åke Borg, Katja Harbst, K. Nielsen, Anita Schmidt Zander, Anders Molvern, Per Helsing, Per Arne Andresen, Helge Rootwelt, Lars A. Akslen, Brigitte Bressac–de Paillerets, Florence Démenais, Marie‐Françoise Avril, Valérie Chaudru, Patricia Jeannin, Fabienne Lesueur, E. Maubec, Hamida Mohamdi, M.J. Bossard, Amaury Vaysse, F. Boitier, Olivier Caron, F. Caux, Stéphane Dalle, O. Dereure, Dominique Leroux, Ludovic Martin, Christine Matéus, Caroline Robert, Dominique Stoppa‐Lyonnet, L. Thomas, E. Wierzbicka, David E. Elder, Michael E. Ming, Nandita Mitra, Tadeusz Dębniak, Jan Lubiński, Marko Hočevar, Srdjan Novaković, Barbara Perić, Petra Škerl, Johan Hansson, Veronica Höiom, Eitan Freidman, Esther Azizi, Orna Baron‐Epel, Alon Scope, Felix Pavlotsky, Irit Cohen‐Manheim, Yael Laitman, Mark Harland, Juliette A. Randerson‐Moor, Jon Laye, John Dwyfor Davies, Jérémie Nsengimana, Sally J. 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 H. Olson, Katherine A. McGlynn, Peter A. Kanetsky, Nilanjan Chatterjee, Jennifer H. Barrett, Alison M. Dunning, John Taylor, Julia Newton‐Bishop, D. Timothy Bishop, Þorkell Andrésson, Gloria M. Petersen, Christopher I. Amos, Mark M. Iles, Katherine L. Nathanson, Maria Teresa Landi, Michiel Vermeulen, Kevin M. Brown, Laufey T. Ámundadóttir,

Chromosomal and Genetic Variations

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.