Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148
Authors: 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 ,   PanScan Consortium, Canzian Federico , Kooperberg Charles , Wang Zhaoming , 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 ,   TRICL Consortium, 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 ,   GenoMEL Consortium, 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 , Gimenez-Xavier Pol , Iglesias-Garcia Pablo , Malvehy Josep , Mila Montse , Pigem Ramon , Potrony Miriam , Puig-Batille Joan Anton , Tell-Marti Gemma , Hayward Nicholas K. , Martin Nicholas G. , Montgomery Grant , Duffy David L. , Whiteman David C. , MacGregor Stuart , Calista Donato , Landi Giorgi , Minghetti Paola , Arcangeli Fabio , Bertazzi Pier Alberto , Ghiorzo Paola , Bianchi-Scarra Giovanna , 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 Håkan , Jönsson Göran , Borg Åke , 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 Olivier , Leroux Dominique , Martin Ludovic , Mateus Christine , Robert Caroline , Stoppa-Lyonnet Dominique , Thomas Luc , Wierzbicka Eva , Elder David E. , Ming Michael , Mitra Nandita , Debniak Tadeusz , Lubinski Jan , Hocevar Marko , Novakovic Srdjan , Peric Barbara , Skerl Petra , Hansson Johan , Höiom 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. 
Published: April 2017

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.