PuSH - Publication Server of Helmholtz Zentrum München: Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of <em>TERT</em> by ZNF148.

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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)

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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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