Fang, JunJia, JinpingMakowski, MatthewXu, MaiWang, ZhaomingZhang, TongwuHoskins, Jason WChoi, JiyeonHan, YounghunZhang, MingfengThomas, JanelleKovacs, MichaelCollins, IreneDzyadyk, MartaThompson, AbbeyO'Neill, MauraDas, SudiptoLan, QiKoster, RoelofStolzenberg-Solomon, Rachael SKraft, PeterWolpin, Brian MJansen, Pascal W T COlson, SaraMcGlynn, Katherine AKanetsky, Peter AChatterjee, NilanjanBarrett, Jennifer HDunning, Alison MTaylor, John CNewton-Bishop, Julia ABishop, D TimothyAndresson, ThorkellPetersen, Gloria MAmos, Christopher IIles, Mark MNathanson, Katherine LLandi, Maria TeresaVermeulen, MichielBrown, Kevin MAmundadottir, Laufey T2018-01-122018-01-122017-05-02Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. 2017, 8:15034 Nat Commun2041-17232844766810.1038/ncomms15034http://hdl.handle.net/10029/621150Genome 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.enArchived with thanks to Nature communicationsNat Commun 2017; 8:15034