Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148.
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Authors
Fang, JunJia, Jinping
Makowski, Matthew
Xu, Mai
Wang, Zhaoming
Zhang, Tongwu
Hoskins, Jason W
Choi, Jiyeon
Han, Younghun
Zhang, Mingfeng
Thomas, Janelle
Kovacs, Michael
Collins, Irene
Dzyadyk, Marta
Thompson, Abbey
O'Neill, Maura
Das, Sudipto
Lan, Qi
Koster, Roelof
Stolzenberg-Solomon, Rachael S
Kraft, Peter
Wolpin, Brian M
Jansen, Pascal W T C
Olson, Sara
McGlynn, Katherine A
Kanetsky, Peter A
Chatterjee, Nilanjan
Barrett, Jennifer H
Dunning, Alison M
Taylor, John C
Newton-Bishop, Julia A
Bishop, D Timothy
Andresson, Thorkell
Petersen, Gloria M
Amos, Christopher I
Iles, Mark M
Nathanson, Katherine L
Landi, Maria Teresa
Vermeulen, Michiel
Brown, Kevin M
Amundadottir, Laufey T
Language
en
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Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148.Published in
Nat Commun 2017; 8:15034Publiekssamenvatting
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.PMID
28447668ae974a485f413a2113503eed53cd6c53
10.1038/ncomms15034
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