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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.

Original publication

DOI

10.1038/ncomms15034

Type

Journal article

Journal

Nature communications

Publication Date

02/05/2017

Volume

8

Addresses

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Keywords

PanScan Consortium, TRICL Consortium, GenoMEL Consortium, Cell Line, Tumor, Chromosomes, Human, Pair 5, Humans, Melanoma, Pancreatic Neoplasms, Testicular Neoplasms, Skin Neoplasms, Lung Neoplasms, Genetic Predisposition to Disease, Telomerase, DNA-Binding Proteins, Histones, Transcription Factors, RNA, Small Interfering, Chromosome Mapping, Signal Transduction, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Alleles, Female, Male, Genome-Wide Association Study, Genetic Loci, Telomere Homeostasis