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oai:recercat.cat:2445/1578482025-11-19T19:05:35Zcom_2072_1057col_2072_478858col_2072_478916col_2072_478917col_2072_478921

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148 Fang, Jun Jia, Jinping Makowski, Matthew Xu, Mai Wang, Zhaoming Zhang, Tongwu Hoskins, Jason W. Carrera Álvarez, Cristina PanScan Consortium TRICL Consortium GenoMEL Consortium Càncer de pulmó Càncer de pell Càncer de pàncrees Genètica Lung cancer Skin cancer Pancreas cancer Genetics 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. 2020-04-28T16:34:16Z 2020-04-28T16:34:16Z 2017-05-02 2020-04-28T16:34:16Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1038/ncomms15034 Nature Communications, 2018, vol. 8, p. 15034 https://doi.org/10.1038/ncomms15034 info:eu-repo/grantAgreement/EC/FP7/607142/EU//DEVCOM cc-by (c) Fang, Jun et al., 2018 http://creativecommons.org/licenses/by/3.0/es info:eu-repo/semantics/openAccess Nature Publishing Group Articles publicats en revistes (Medicina)