| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Priority Reports |
1 Arizona Cancer Center, 2 Department of Pharmacology and Toxicology, 3 Arizona Respiratory Center, and 4 Department of Surgery, University of Arizona, Tucson, Arizona; and 5 Institute of Plant Molecular Biology AS CR, Ceske Budejovice, Czech Republic
Requests for reprints: Bernard W. Futscher, Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724. Phone: 520-626-4646; Fax: 520-626-2415; E-mail: bfutscher{at}azcc.arizona.edu.
Using an integrated approach of epigenomic scanning and gene expression profiling, we found aberrant methylation and epigenetic silencing of a small neighborhood of contiguous genes—the HOXA gene cluster in human breast cancer. The observed transcriptional repression was localized to 
100 kb of the HOXA gene cluster and did not extend to genes located upstream or downstream of the cluster. Bisulfite sequencing, chromatin immunoprecipitation, and quantitative reverse transcription-PCR analysis confirmed that the loss of expression of the HOXA gene cluster in human breast cancer is closely linked to aberrant DNA methylation and loss of permissive histone modifications in the region. Pharmacologic manipulations showed the importance of these aberrant epigenetic changes in gene silencing and support the hypothesis that aberrant DNA methylation is dominant to histone hypoacetylation. Overall, these data suggest that inactivation of the HOXA gene cluster in breast cancer may represent a new type of genomic lesion—epigenetic microdeletion. We predict that epigenetic microdeletions are common in human cancer and that they functionally resemble genetic microdeletions but are defined by epigenetic inactivation and transcriptional silencing of a relatively small set of contiguous genes along a chromosome, and that this type of genomic lesion is metastable and reversible in a classic epigenetic fashion. (Cancer Res 2006; 66(22): 10664-70)
This article has been cited by other articles:
|
|
 |
|
  T. J. Jensen, P. Novak, K. E. Eblin, A. J. Gandolfi, and B. W. Futscher Epigenetic remodeling during arsenical-induced malignant transformation Carcinogenesis, August 1, 2008; 29(8): 1500 - 1508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wu, Y. Gong, J. Yue, B. Qiang, J. Yuan, and X. Peng Cooperation between EZH2, NSPc1-mediated histone H2A ubiquitination and Dnmt1 in HOX gene silencing Nucleic Acids Res., June 1, 2008; 36(11): 3590 - 3599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. C. Cho A future of cancer prevention and cures: highlights of the Centennial Meeting of the American Association for Cancer Research Ann. Onc., February 1, 2008; 19(2): 205 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Hitchins, V. A. Lin, A. Buckle, K. Cheong, N. Halani, S. Ku, C.-T. Kwok, D. Packham, C. M. Suter, A. Meagher, et al. Epigenetic Inactivation of a Cluster of Genes Flanking MLH1 in Microsatellite-Unstable Colorectal Cancer Cancer Res., October 1, 2007; 67(19): 9107 - 9116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Clark Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis Hum. Mol. Genet., April 15, 2007; 16(R1): R88 - R95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Brena and J. F. Costello Genome-epigenome interactions in cancer Hum. Mol. Genet., April 15, 2007; 16(R1): R96 - R105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Rauch, Z. Wang, X. Zhang, X. Zhong, X. Wu, S. K. Lau, K. H. Kernstine, A. D. Riggs, and G. P. Pfeifer Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay PNAS, March 27, 2007; 104(13): 5527 - 5532. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
