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

2.50
Hdl Handle:
http://hdl.handle.net/10029/621150
Title:
Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148.
Authors:
Fang, Jun; Jia, 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
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.
Citation:
Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. 2017, 8:15034 Nat Commun
Journal:
Nat Commun 2017; 8:15034
Issue Date:
2-May-2017
URI:
http://hdl.handle.net/10029/621150
DOI:
10.1038/ncomms15034
PubMed ID:
28447668
Language:
en
ISSN:
2041-1723
Appears in Collections:
Miscellaneous

Full metadata record

DC FieldValue Language
dc.contributor.authorFang, Junen
dc.contributor.authorJia, Jinpingen
dc.contributor.authorMakowski, Matthewen
dc.contributor.authorXu, Maien
dc.contributor.authorWang, Zhaomingen
dc.contributor.authorZhang, Tongwuen
dc.contributor.authorHoskins, Jason Wen
dc.contributor.authorChoi, Jiyeonen
dc.contributor.authorHan, Younghunen
dc.contributor.authorZhang, Mingfengen
dc.contributor.authorThomas, Janelleen
dc.contributor.authorKovacs, Michaelen
dc.contributor.authorCollins, Ireneen
dc.contributor.authorDzyadyk, Martaen
dc.contributor.authorThompson, Abbeyen
dc.contributor.authorO'Neill, Mauraen
dc.contributor.authorDas, Sudiptoen
dc.contributor.authorLan, Qien
dc.contributor.authorKoster, Roelofen
dc.contributor.authorStolzenberg-Solomon, Rachael Sen
dc.contributor.authorKraft, Peteren
dc.contributor.authorWolpin, Brian Men
dc.contributor.authorJansen, Pascal W T Cen
dc.contributor.authorOlson, Saraen
dc.contributor.authorMcGlynn, Katherine Aen
dc.contributor.authorKanetsky, Peter Aen
dc.contributor.authorChatterjee, Nilanjanen
dc.contributor.authorBarrett, Jennifer Hen
dc.contributor.authorDunning, Alison Men
dc.contributor.authorTaylor, John Cen
dc.contributor.authorNewton-Bishop, Julia Aen
dc.contributor.authorBishop, D Timothyen
dc.contributor.authorAndresson, Thorkellen
dc.contributor.authorPetersen, Gloria Men
dc.contributor.authorAmos, Christopher Ien
dc.contributor.authorIles, Mark Men
dc.contributor.authorNathanson, Katherine Len
dc.contributor.authorLandi, Maria Teresaen
dc.contributor.authorVermeulen, Michielen
dc.contributor.authorBrown, Kevin Men
dc.contributor.authorAmundadottir, Laufey Ten
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.en
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

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