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

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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.

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