Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
van Doorn
Remco
R
Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
Zoutman
Willem H
WH
Dijkman
Remco
R
de Menezes
Renee X
RX
Commandeur
Suzan
S
Mulder
Aat A
AA
van der Velden
Pieter A
PA
Vermeer
Maarten H
MH
Willemze
Rein
R
Yan
Pearlly S
PS
Huang
Tim H
TH
Tensen
Cornelis P
CP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D015894:Genome, Human; D006801:Humans; D017730:Ki-1 Antigen / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics*; D008297:Male; D046228:Microarray Analysis; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D012878:Skin Neoplasms / Q000235:genetics*; D019699:Thrombospondins / Q000235:genetics; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
C098982:BCL7A protein, human; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D017730:Ki-1 Antigen; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C000606460:TP73 protein, human; D019699:Thrombospondins; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C101864:thrombospondin 4; C516850:PTPRG protein, human; D017027:Protein Tyrosine Phosphatases; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5