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Nature Research, Nature Communications, 1(8), 2017

DOI: 10.1038/ncomms15034

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Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Journal article published in 2017 by Wei Zheng, Frans A. van Nieuwpoort, Nienke van der Stoep, Jeanet ter Huurne, Han van der Rhee, Marinus van Praag, Jason W. Hoskins, Jun Fang, Jinping Jia, Maura O’Neill, Sudipto Das, Qi Lan, Roelof Koster ORCID, Federico Canzian, Charles Kooperberg and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

AbstractGenome 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.