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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Contributor PanScan Consortium, TRICL Consortium, GenoMel Consortium
Persistent URL dx.doi.org/10.1038/ncomms15034, hdl.handle.net/1765/103663
Journal Nature Communications
Citation
Fang, J. (Jun), Jia, J. (Jinping), Makowski, M. (Matthew), Xu, M. (Mai), Wang, Z, Zhang, T. (Tongwu), … Amundadottir, L.T. (Laufey T.). (2017). Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. Nature Communications, 8. doi:10.1038/ncomms15034