Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148.
dc.contributor.author | Fang, Jun | |
dc.contributor.author | Jia, Jinping | |
dc.contributor.author | Makowski, Matthew | |
dc.contributor.author | Xu, Mai | |
dc.contributor.author | Wang, Zhaoming | |
dc.contributor.author | Zhang, Tongwu | |
dc.contributor.author | Hoskins, Jason W | |
dc.contributor.author | Choi, Jiyeon | |
dc.contributor.author | Han, Younghun | |
dc.contributor.author | Zhang, Mingfeng | |
dc.contributor.author | Thomas, Janelle | |
dc.contributor.author | Kovacs, Michael | |
dc.contributor.author | Collins, Irene | |
dc.contributor.author | Dzyadyk, Marta | |
dc.contributor.author | Thompson, Abbey | |
dc.contributor.author | O'Neill, Maura | |
dc.contributor.author | Das, Sudipto | |
dc.contributor.author | Lan, Qi | |
dc.contributor.author | Koster, Roelof | |
dc.contributor.author | Stolzenberg-Solomon, Rachael S | |
dc.contributor.author | Kraft, Peter | |
dc.contributor.author | Wolpin, Brian M | |
dc.contributor.author | Jansen, Pascal W T C | |
dc.contributor.author | Olson, Sara | |
dc.contributor.author | McGlynn, Katherine A | |
dc.contributor.author | Kanetsky, Peter A | |
dc.contributor.author | Chatterjee, Nilanjan | |
dc.contributor.author | Barrett, Jennifer H | |
dc.contributor.author | Dunning, Alison M | |
dc.contributor.author | Taylor, John C | |
dc.contributor.author | Newton-Bishop, Julia A | |
dc.contributor.author | Bishop, D Timothy | |
dc.contributor.author | Andresson, Thorkell | |
dc.contributor.author | Petersen, Gloria M | |
dc.contributor.author | Amos, Christopher I | |
dc.contributor.author | Iles, Mark M | |
dc.contributor.author | Nathanson, Katherine L | |
dc.contributor.author | Landi, Maria Teresa | |
dc.contributor.author | Vermeulen, Michiel | |
dc.contributor.author | Brown, Kevin M | |
dc.contributor.author | Amundadottir, Laufey T | |
dc.date.accessioned | 2018-01-12T08:56:11Z | |
dc.date.available | 2018-01-12T08:56:11Z | |
dc.date.issued | 2017-05-02 | |
dc.identifier.citation | Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. 2017, 8:15034 Nat Commun | en |
dc.identifier.issn | 2041-1723 | |
dc.identifier.pmid | 28447668 | |
dc.identifier.doi | 10.1038/ncomms15034 | |
dc.identifier.uri | http://hdl.handle.net/10029/621150 | |
dc.description.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. | |
dc.language.iso | en | en |
dc.rights | Archived with thanks to Nature communications | en |
dc.title | Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. | en |
dc.identifier.journal | Nat Commun 2017; 8:15034 | en |
html.description.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. |