Author/Editor | Fang, Jun; Hočevar, Marko; Novaković, Srdjan; Perić, Barbara; Škerl, Petra | |
Title | Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148 | |
Type | članek | |
Vol. and No. | , št. Vol. 8 | |
Publication year | 2017 | |
ISSN | 2041-1723 - Nature communications | |
Language | eng | |
Abstract | 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. | |
Keywords | tveganje za raka genomi mutacije karcinogeneza multi-cancer risk genomes mutations carcinogenesis |