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.
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; PanScan Consortium; TRICL Consortium; GenoMEL Consortium; 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; Peterson, Gloria M.; and Amos, Christopher I., "Functional Characterization of a Multi-Cancer Risk Locus on Chr5p15.33 Reveals Regulation of Tert by Znf148" (2017). Open Dartmouth: Faculty Open Access Articles. 2706.