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Get Free AccessGenome 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.
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 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 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 (2017). Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. , 8(1), DOI: https://doi.org/10.1038/ncomms15034.
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Type
Article
Year
2017
Authors
100
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.1038/ncomms15034
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