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

   

Authors:	Fang, J.; Jia, J.; Makowski, M.; Xu, M.; Wang, Z.; Zhang, T.; Hoskins, J. W.; Choi, J.; Han, Y.; Zhang, M.; Thomas, J.; Kovacs, M.; Collins, I.; Dzyadyk, M.; Thompson, A.; O'Neill, M.; Das, S.; Lan, Q.; Koster, R.; PanScan Consortium; TRICL Consortium; GenoMEL Consortium; Stolzenberg-Solomon, R. S.; Kraft, P.; Wolpin, B. M.; Jansen, P. W. T. C.; Olson, S.; McGlynn, K. A.; Kanetsky, P. A.; Chatterjee, N.; Barrett, J. H.; Dunning, A. M.; Taylor, J. C.; Newton-Bishop, J. A.; Bishop, D. T.; Andresson, T.; Petersen, G. M.; Amos, C. I.; Iles, M. M.; Nathanson, K. L.; Landi, M. T.; Vermeulen, M.; Brown, K. M.; Amundadottir, L. T.
Contributor:	Kurtz, R. C.
Article Title:	Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148
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. © The Author(s) 2017.
Keywords:	controlled study; protein expression; functional assessment; unclassified drug; human cell; major clinical study; single nucleotide polymorphism; cancer risk; pancreas cancer; allele; melanoma; gene expression; protein; protein binding; gene locus; genome-wide association study; lung cancer; enzyme activity; proteomics; risk assessment; regulatory mechanism; telomerase reverse transcriptase; gene silencing; testis cancer; zinc finger protein; chemical binding; telomere length; cancer; human; article; zinc finger protein 148
Journal Title:	Nature Communications
Volume:	8
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2017-05-02
Start Page:	15034
Language:	English
DOI:	10.1038/ncomms15034
PROVIDER:	scopus
PMCID:	PMC5414179
PUBMED:	28447668
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85038930539&doi=10.1038%2fncomms15034&partnerID=40&md5=27e7fe4699bf96e59de02f97b5dae69a
Notes:	Article -- Export Date: 1 February 2018 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/120533