Authors

Jun Fang, National Cancer Institute, National Institutes of Health, Maryland
Jinping Jia, National Cancer Institute, National Institutes of Health, Maryland
Matthew Makowski, Radboud University
Mai Xu, National Cancer Institute, National Institutes of Health, Maryland
Zhaoming Wang, National Cancer Institute, National Institutes of Health, Maryland
Tongwu Zhang, National Cancer Institute, National Institutes of Health, Maryland
Jason W. Hoskins, National Cancer Institute, National Institutes of Health, Maryland
Jiyeon Choi, National Cancer Institute, National Institutes of Health, Maryland
Younghun Han, Dartmouth College
Mingfeng Zhang, National Cancer InstituteNational Institutes of Health, Maryland
Janelle Thomas, National Cancer Institute, National Institutes of Health, Maryland
Michael Kovacs, National Cancer Institute, National Institutes of Health, Maryland
Irene Collins, National Cancer Institute, National Institutes of Health, Maryland
Marta Dzyadyk, National Cancer Institute, National Institutes of Health, Maryland
Abbey Thompson, National Cancer Institute, National Institutes of Health, Maryland
Maura O'Neill, Frederick National Laboratory for Cancer Research, Maryland
Sudipto Das, Frederick National Laboratory for Cancer Research, Maryland
Qi Lan, National Cancer Institute, National Institutes of Health, Maryland
Roelof Koster, National Cancer Institute, National Institutes of Health, Maryland
PanScan Consortium
TRICL Consortium
GenoMEL Consortium
Rachael S. Stolzenberg-Solomon, National Cancer Institute, National Institutes of Health, Maryland
Peter Kraft, Harvard School of Public Health
Brian M. Wolpin, Harvard School of Public Health
Pascal W.T.C Jansen, Radboud University
Sara Olson, Memorial Sloan-Kettering Cancer Center, New York
Katherine A. McGlynn, National Cancer Institute, National Institutes of Health, Maryland
Peter A. Kanetsky, H. Lee Moffitt Cancer Center and Research Institute, Florida
Nilanjan Chatterjee, National Cancer Institute, National Institutes of Health, Maryland
Jennifer H. Barrett, University of Leeds
Alison M. Dunning, University of Cambridge
John C. Taylor, University of Leeds
Julia A. Newton-Bishop, University of Leeds
D. Timothy Bishop, University of Leeds
Thorkell Andresson, Frederick National Laboratory for Cancer Research, Maryland
Gloria M. Peterson, Mayo Clinic, Rochester, Minnesota
Christopher I. Amos, Dartmouth College

Document Type

Article

Publication Date

5-2-2017

Publication Title

Nature Communications

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.

DOI

10.1038/ncomms15034

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