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Fang, J.C.* ; Jia, J.* ; Makowski, M.* ; Xu, M.* ; Wang, Z.* ; Zhang, T.* ; Hoskins, J.W.* ; Choi, J.H.* ; Han, Y.* ; Zhang, M.* ; Thomas, J.A.* ; Kovacs, M.* ; Collins, I.* ; Dzyadyk, M.* ; Thompson, A.* ; O'Neill, M.* ; Das, S.* ; Lan, Q.* ; Köster, R.* ; Stolzenberg-Solomon, R.S.* ; Kraft, P.* ; Wolpin, B.M.* ; Jansen, P.W.T.C.* ; Olson, S.H.* ; 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.* ; TRICL Consortium (Wichmann, H.-E.) ; Brown, K.M.* ; Amundadottir, L.T.*

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

Nat. Commun. 8:15034 (2017)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 8, Heft: , Seiten: , Artikelnummer: 15034 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)
Institute of Epidemiology II (EPI2)