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-SolomonPeter 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, Laufey T Amundadottir, PanScan Consortium, Vittorio Krogh

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)15034
JournalNature Communications
Volume8
DOIs
Publication statusPublished - May 2 2017

Keywords

  • Journal Article

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