Originally published as JCO Early Release 10.1200/JCO.2005.11.353 on May 16 2005

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Doorn, R. Articles by Tensen, C. P. Search for Related Content PubMed PubMed Citation Articles by van Doorn, R. Articles by Tensen, C. P.

Epigenetic Profiling of Cutaneous T-Cell Lymphoma: Promoter Hypermethylation of Multiple Tumor Suppressor Genes Including BCL7a, PTPRG, and p73

Remco van Doorn, Willem H. Zoutman, Remco Dijkman, Renee X. de Menezes, Suzan Commandeur, Aat A. Mulder, Pieter A. van der Velden, Maarten H. Vermeer, Rein Willemze, Pearlly S. Yan, Tim H. Huang, Cornelis P. Tensen

From the Departments of Dermatology and Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands; and Division of Human Cancer Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH

Address reprint requests to Cornelius P. Tensen, MD, Leiden University Medical Center, Dermatology, Wassenaarseweg 72, Leiden ZH 2333AL, the Netherlands; e-mail: c.p.tensen{at}lumc.nl.

PURPOSE: To analyze the occurrence of promoter hypermethylation in primary cutaneous T-cell lymphoma (CTCL) on a genome-wide scale, focusing on epigenetic alterations with pathogenetic significance.

MATERIALS AND METHODS: DNA isolated from biopsy specimens of 28 patients with CTCL, including aggressive CTCL entities (transformed mycosis fungoides and CD30-negative large T-cell lymphoma) and an indolent entity (CD30-positive large T-cell lymphoma), were investigated. For genome-wide DNA methylation screening, differential methylation hybridization using CpG island microarrays was applied, which allows simultaneous detection of the methylation status of 8640 CpG islands. Bisulfite sequence analysis was applied for confirmation and detection of hypermethylation of eight selected tumor suppressor genes.

RESULTS: The DNA methylation patterns of CTCLs emerging from differential methylation hybridization analysis included 35 CpG islands hypermethylated in at least four of the 28 studied CTCL samples when compared with benign T-cell samples. Hypermethylation of the putative tumor suppressor genes BCL7a (in 48% of CTCL samples), PTPRG (27%), and thrombospondin 4 (52%) was confirmed and demonstrated to be associated with transcriptional downregulation. BCL7a was hypermethylated at a higher frequency in aggressive (64%) than in indolent (14%) CTCL entities. In addition, the promoters of the selected tumor suppressor genes p73 (48%), p16 (33%), CHFR (19%), p15 (10%), and TMS1 (10%) were hypermethylated in CTCL.

CONCLUSION: Malignant T cells of patients with CTCL display widespread promoter hypermethylation associated with inactivation of several tumor suppressor genes involved in DNA repair, cell cycle, and apoptosis signaling pathways. In view of this, CTCL may be amenable to treatment with demethylating agents.

R. van Doorn was supported by a Genomics Fellowship, awarded by the Netherlands Organization for Scientific Research.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

This article has been cited by other articles:

				S. Pfister, C. Schlaeger, F. Mendrzyk, A. Wittmann, A. Benner, A. Kulozik, W. Scheurlen, B. Radlwimmer, and P. Lichter Array-based profiling of reference-independent methylation status (aPRIMES) identifies frequent promoter methylation and consecutive downregulation of ZIC2 in pediatric medulloblastoma Nucleic Acids Res., April 1, 2007; 35(7): e51 - e51. [Abstract] [Full Text] [PDF]

				A. L. Carvalho, A. Chuang, W.-W. Jiang, J. Lee, S. Begum, L. Poeta, M. Zhao, C. Jeronimo, R. Henrique, C. S. Nayak, et al. Deleted in Colorectal Cancer Is a Putative Conditional Tumor-Suppressor Gene Inactivated by Promoter Hypermethylation in Head and Neck Squamous Cell Carcinoma Cancer Res., October 1, 2006; 66(19): 9401 - 9407. [Abstract] [Full Text] [PDF]

				Q. Zhang, H. Y. Wang, A. Woetmann, P. N. Raghunath, N. Odum, and M. A. Wasik STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes Blood, August 1, 2006; 108(3): 1058 - 1064. [Abstract] [Full Text] [PDF]

				D. Bhojwani, H. Kang, N. P. Moskowitz, D.-J. Min, H. Lee, J. W. Potter, G. Davidson, C. L. Willman, M. J. Borowitz, I. Belitskaya-Levy, et al. Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children's Oncology Group study Blood, July 15, 2006; 108(2): 711 - 717. [Abstract] [Full Text] [PDF]

				J. Furuta, Y. Nobeyama, Y. Umebayashi, F. Otsuka, K. Kikuchi, and T. Ushijima Silencing of peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas. Cancer Res., June 15, 2006; 66(12): 6080 - 6086. [Abstract] [Full Text] [PDF]

				R. Dijkman, C. P. Tensen, E. S. Jordanova, J. Knijnenburg, J. J. Hoefnagel, A. A. Mulder, C. Rosenberg, A. K. Raap, R. Willemze, K. Szuhai, et al. Array-Based Comparative Genomic Hybridization Analysis Reveals Recurrent Chromosomal Alterations and Prognostic Parameters in Primary Cutaneous Large B-Cell Lymphoma J. Clin. Oncol., January 10, 2006; 24(2): 296 - 305. [Abstract] [Full Text] [PDF]