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Tumor-associated Zinc Finger Mutations in the CTCF Transcription Factor Selectively Alter Its DNA-binding Specificity¹

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 [G. N. F., J. E. U., J. M. M., M. D. W., Y. J. H., P. E. N., S. J. C.]; Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892 [C. F. Q., D. I. L., E. M. P., H. C. M., V. V. L.]; Department of Biological Sciences, University of Essex, Essex CO4 3SQ, United Kingdom [E. M. K.]; Cross Cancer Institute, Edmonton, Alberta, T6G 1Z2 Canada [P. E. G.]; Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 [A. P. F.]; Department of Pathology, University of Leiden, NL-2300 RA Leiden, the Netherlands [A-M. C-J., E. W. M., C. J. C.]; Department of Urology, School of Medicine, Chiba University, Chiba 260, Japan [H. S., A. K.]; Department of Clinical Genetics, Karolinska Hospital, 510401 Stockholm, Sweden [A. L.]; and Laboratoire de Génétique Moléculaire, Institut Bergonié, 33076 Bordeaux, France [F. D-B.]

CTCF is a widely expressed 11-zinc finger (ZF) transcription factor that is involved in different aspects of gene regulation including promoter activation or repression, hormone-responsive gene silencing, methylation-dependent chromatin insulation, and genomic imprinting. Because CTCF targets include oncogenes and tumor suppressor genes, we screened over 100 human tumor samples for mutations that might disrupt CTCF activity. We did not observe any CTCF mutations leading to truncations/premature stops. Rather, in breast, prostate, and Wilms’ tumors, we observed four different CTCF somatic missense mutations involving amino acids within the ZF domain. Each ZF mutation abrogated CTCF binding to a subset of target sites within the promoters/insulators of certain genes involved in regulating cell proliferation but did not alter binding to the regulatory sequences of other genes. These observations suggest that CTCF may represent a novel tumor suppressor gene that displays tumor-specific "change of function" rather than complete "loss of function."

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