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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/157848
Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148
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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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FANG, Jun, JIA, Jinping, MAKOWSKI, Matthew, XU, Mai, WANG, Zhaoming, ZHANG, Tongwu, HOSKINS, Jason w., CARRERA ÁLVAREZ, Cristina, PanScan Consortium, TRICL Consortium, GenoMEL Consortium. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. _Nature Communications_. 2018. Vol. 8, núm. 15034. [consulta: 27 de gener de 2026]. ISSN: 2041-1723. [Disponible a: https://hdl.handle.net/2445/157848]