학술논문
Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148
Document Type
Journal Article
Author
Fang, Jun; Jia, Jinping; Makowski, Matthew; Xu, Mai; Wang, Zhaoming; Zhang, Tongwu; Hoskins, Jason W.; Choi, Jiyeon; Han, Younghun; Zhang, Mingfeng; Thomas, Janelle; Kovacs, Michael; Collins, Irene; Dzyadyk, Marta; Thompson, Abbey; O'Neill, Maura; Das, Sudipto; Lan, Qi; Koster, Roelof; Canzian, Federico; Kooperberg, Charles; Arslan, Alan A; Bracci, Paige M; Buring, Julie; Duell, Eric J; Gallinger, Steven; Jacobs, Eric J; Kamineni, Aruna; Van Den Eeden, Stephen; Klein, Alison P; Kolonel, Laurence N; Li, Donghui; Olson, Sara H; Risch, Harvey A; Sesso, Howard D; Visvanathan, Kala; Zheng, Wei; Albanes, Demetrius; Austin, Melissa A; Boutron-Ruault, Marie-Christine; Bueno-de-Mesquita, H Bas; Cotterchio, Michelle; Gaziano, J Michael; Giovannucci, Edward L; Goggins, Michael; Gross, Myron; Hassan, Manal; Helzlsouer, Kathy J; Holly, Elizabeth A; Hunter, David J; Jenab, Mazda; Kaaks, Rudolf; Key, Timothy J; Khaw, Kay-Tee; Krogh, Vittorio; Kurtz, Robert C; LaCroix, Andrea; Le Marchand, Loic; Mannisto, Satu; Patel, Alpa V; Peeters, Petra H M; Riboli, Elio; Shu, Xiao-Ou; Sund, Malin; Thornquist, Mark; Tjønneland, Anne; Tobias, Geoffrey S; Trichopoulos, Dimitrios; Wactawski-Wende, Jean; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Hoover, Robert; Hartge, Patricia; Fuchs, Charles; Chanock, Stephen J; Stevens, Victoria; Albanes, Demetrios; Caporaso, Neil E; Brennan, Paul; McKay, James; Wu, Xifeng; Hung, Rayjean J; McLaughlin, John R; Bickeboller, Heike; Risch, Angela; Wichmann, Erich; Houlston, Richard; Mann, Graham; Hopper, John; Aitken, Joanne; Armstrong, Bruce; Giles, Graham; Holland, Elizabeth; Kefford, Richard; Cust, Anne; Jenkins, Mark; Schmid, Helen; Puig, Susana; Aguilera, Paula; Badenas, Celia; Barreiro, Alicia; Carrera, Cristina; Gabriel, Daniel; Xavier, Pol Gimenez; Iglesias-Garcia, Pablo; Malvehy, Josep; Mila, Montse; Pigem, Ramon; Potrony, Miriam; Batille, Joan-AntonPuig; Marti, Gemma Tell; Hayward, Nick; Martin, Nicholas; Montgomery, Grant; Duffy, David; Whiteman, David; Gregor, Stuart Mac; Calista, Donato; Landi, Giorgi; Minghetti, Paola; Arcangeli, Fabio; Bertazzi, Pier Alberto; Ghiorzo, Paola; Scarra, Giovanna Bianchi; Pastorino, Lorenze; Bruno, William; Andreotti, Virginia; Queirolo, Paola; Spagnolo, Francesco; Mackie, Rona; Lang, Julie; Gruis, Nelleke; van Nieuwpoort, Frans A; Out, Coby; Bergman, Wilma; Kukutsch, Nicole; Bavinck, Jan Nico Bouwes; Bakker, Bert; van der Stoep, Nienke; ter Huurne, Jeanet; van der Rhee, Han; Bekkenk, Marcel; Snels, Dyon; van Praag, Marinus; Brochez, Lieve; Gerritsen, Rianne; Crijns, Marianne; Vasen, Hans; Janssen, Bart; Ingvar, Christian; Olsson, Hakan; Jonsson, Goran; Borg, Ake; Harbst, Katja; Nielsen, Kari; Zander, Anita Schmidt; Molvern, Anders; Helsing, Per; Andresen, Per Arne; Rootwelt, Helge; Akslen, Lars A; Bressac-de Paillerets, Brigitte; Demenais, Florence; Avril, Marie-Francoise; Chaudru, Valerie; Jeannin, Patricia; Lesueur, Fabienne; Maubec, Eve; Mohamdi, Hamida; Bossard, Myriam; Vaysse, Amaury; Boitier, Francoise; Caron, Oliver; Caux, Frederic; Dalle, Stephane; Dereure, Oliviier; Leroux, Dominique; Martin, Ludovic; Mateus, Christine; Robert, Caroline; Stoppa-Lyonnet, Dominique; Thomas, Luc; Wierzbicka, Eva; Elder, David; Ming, Michael; Mitra, Nandita; Debniak, Tadeusz; Lubinski, Jan; Hocevar, Marko; Novakovic, Srdjan; Peric, Barbara; Skerl, Petra; Hansson, Johan; Hoiom, Veronica; Freidman, Eitan; Azizi, Esther; Baron-Epel, Orna; Scope, Alon; Pavlotsky, Felix; Cohen-Manheim, Irit; Laitman, Yael; Harland, Mark; Randerson-Moor, Juliette; Laye, Jon; Davies, John; Nsengimana, Jeremie; O'Shea, Sally; Chan, May; Gascoyne, Jo; Tucker, Margaret A; Goldstein, Alisa M; Yang, Xiaohong R; Stolzenberg-Solomon, Rachael S.; Kraft, Peter; Wolpin, Brian M.; Jansen, Pascal W. T. C.; Olson, Sara; McGlynn, Katherine A.; Kanetsky, Peter A.; Chatterjee, Nilanjan; Barrett, Jennifer H.; Dunning, Alison M.; Taylor, John C.; Newton-Bishop, Julia A.; Bishop, D. Timothy; Andresson, Thorkell; Petersen, Gloria M.; Amos, Christopher I.; Iles, Mark M.; Nathanson, Katherine L.; Landi, Maria Teresa; Vermeulen, Michiel; Brown, Kevin M.; Amundadottir, Laufey T.
Source
Fang, J., J. Jia, M. Makowski, M. Xu, Z. Wang, T. Zhang, J. W. Hoskins, et al. 2017. “Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148.” Nature Communications 8 (1): 15034. doi:10.1038/ncomms15034. http://dx.doi.org/10.1038/ncomms15034.
Subject
Language
English
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.