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Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148.
Pubmed ID
28447668 (View this publication on the PubMed website)
Digital Object Identifier
Nat Commun. 2017 May 2; Volume 8: Pages 15034
Fang J, Jia J, Makowski M, Xu M, Wang Z, Zhang T, Hoskins JW, Choi J, Han Y, Zhang M, Thomas J, Kovacs M, Collins I, Dzyadyk M, Thompson A, O'Neill M, Das S, Lan Q, Koster R, PanScan Consortium, more TRICL Consortium, GenoMEL Consortium, Stolzenberg-Solomon RS, Kraft P, Wolpin BM, Jansen PWTC, Olson S, McGlynn KA, Kanetsky PA, Chatterjee N, Barrett JH, Dunning AM, Taylor JC, Newton-Bishop JA, Bishop DT, Andresson T, Petersen GM, Amos CI, Iles MM, Nathanson KL, Landi MT, Vermeulen M, Brown KM, Amundadottir LT
  • Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756, USA.
  • Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701, USA.
  • Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
  • Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen 6500 HB, The Netherlands.
  • Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York City, New York 10065, USA.
  • Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
  • Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK. more
  • Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK.
  • Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
  • Translational Medicine and Human Genetics, Department of Medicine and Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

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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