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Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148.
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2017 (Engelska)Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikel-id 15034Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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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2017. Vol. 8, artikel-id 15034
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Kirurgi
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URN: urn:nbn:se:umu:diva-154588DOI: 10.1038/ncomms15034PubMedID: 28447668OAI: oai:DiVA.org:umu-154588DiVA, id: diva2:1272816
Tillgänglig från: 2018-12-19 Skapad: 2018-12-19 Senast uppdaterad: 2018-12-19

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