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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

Nat Commun

Publication Date

02/05/2017

Volume

8

Keywords

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