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-Solomon, Peter 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 () and Laufey T. Amundadottir ()
Additional contact information
Jun Fang: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Jinping Jia: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Matthew Makowski: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Mai Xu: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Zhaoming Wang: National Cancer Institute, National Institutes of Health
Tongwu Zhang: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Jason W. Hoskins: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Jiyeon Choi: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Younghun Han: Geisel School of Medicine, Dartmouth College
Mingfeng Zhang: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Janelle Thomas: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Michael Kovacs: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Irene Collins: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Marta Dzyadyk: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Abbey Thompson: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Maura O'Neill: Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research
Sudipto Das: Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research
Qi Lan: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Roelof Koster: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Rachael S. Stolzenberg-Solomon: National Cancer Institute, National Institutes of Health
Peter Kraft: Harvard School of Public Health
Brian M. Wolpin: Dana-Farber Cancer Institute
Pascal W. T. C. Jansen: Radboud Institute for Molecular Life Sciences, Radboud University
Sara Olson: Memorial Sloan-Kettering Cancer Center
Katherine A. McGlynn: National Cancer Institute, National Institutes of Health
Peter A. Kanetsky: H. Lee Moffitt Cancer Center and Research Institute
Nilanjan Chatterjee: National Cancer Institute, National Institutes of Health
Jennifer H. Barrett: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds
Alison M. Dunning: University of Cambridge
John C. Taylor: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds
Julia A. Newton-Bishop: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds
D. Timothy Bishop: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds
Thorkell Andresson: Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research
Gloria M. Petersen: Mayo Clinic
Christopher I. Amos: Geisel School of Medicine, Dartmouth College
Mark M. Iles: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds
Katherine L. Nathanson: Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania
Maria Teresa Landi: National Cancer Institute, National Institutes of Health
Michiel Vermeulen: Radboud Institute for Molecular Life Sciences, Radboud University
Kevin M. Brown: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Laufey T. Amundadottir: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15034

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