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dc.contributor.authorFang, Jun
dc.contributor.authorJia, Jinping
dc.contributor.authorMakowski, Matthew
dc.contributor.authorXu, Mai
dc.contributor.authorWang, Zhaoming
dc.contributor.authorZhang, Tongwu
dc.contributor.authorHoskins, Jason W
dc.contributor.authorChoi, Jiyeon
dc.contributor.authorHan, Younghun
dc.contributor.authorZhang, Mingfeng
dc.contributor.authorThomas, Janelle
dc.contributor.authorKovacs, Michael
dc.contributor.authorCollins, Irene
dc.contributor.authorDzyadyk, Marta
dc.contributor.authorThompson, Abbey
dc.contributor.authorO'Neill, Maura
dc.contributor.authorDas, Sudipto
dc.contributor.authorLan, Qi
dc.contributor.authorKoster, Roelof
dc.contributor.authorStolzenberg-Solomon, Rachael S
dc.contributor.authorKraft, Peter
dc.contributor.authorWolpin, Brian M
dc.contributor.authorJansen, Pascal W T C
dc.contributor.authorOlson, Sara
dc.contributor.authorMcGlynn, Katherine A
dc.contributor.authorKanetsky, Peter A
dc.contributor.authorChatterjee, Nilanjan
dc.contributor.authorBarrett, Jennifer H
dc.contributor.authorDunning, Alison M
dc.contributor.authorTaylor, John C
dc.contributor.authorNewton-Bishop, Julia A
dc.contributor.authorBishop, D Timothy
dc.contributor.authorAndresson, Thorkell
dc.contributor.authorPetersen, Gloria M
dc.contributor.authorAmos, Christopher I
dc.contributor.authorIles, Mark M
dc.contributor.authorNathanson, Katherine L
dc.contributor.authorLandi, Maria Teresa
dc.contributor.authorVermeulen, Michiel
dc.contributor.authorBrown, Kevin M
dc.contributor.authorAmundadottir, Laufey T
dc.date.accessioned2018-01-12T08:56:11Z
dc.date.available2018-01-12T08:56:11Z
dc.date.issued2017-05-02
dc.identifier.citationFunctional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. 2017, 8:15034 Nat Communen
dc.identifier.issn2041-1723
dc.identifier.pmid28447668
dc.identifier.doi10.1038/ncomms15034
dc.identifier.urihttp://hdl.handle.net/10029/621150
dc.description.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.
dc.language.isoenen
dc.rightsArchived with thanks to Nature communicationsen
dc.titleFunctional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148.en
dc.identifier.journalNat Commun 2017; 8:15034en
html.description.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.


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