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, Hui-ming Huang, Cornelis P. Tensen

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3886-3896
Number of pages11
JournalJournal of Clinical Oncology
Volume23
Issue number17
DOIs
StatePublished - 2005
Externally publishedYes

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Cutaneous T-Cell Lymphoma
Tumor Suppressor Genes
Epigenomics
CpG Islands
Methylation
T-Cell Lymphoma
DNA Methylation
Genome
T-Lymphocytes
Mycosis Fungoides
DNA Repair
Sequence Analysis
Cell Cycle
Down-Regulation
Apoptosis
Biopsy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Van Doorn, R., Zoutman, W. H., Dijkman, R., De Menezes, R. X., Commandeur, S., Mulder, A. A., ... Tensen, C. P. (2005). Epigenetic profiling of cutaneous T-cell lymphoma: Promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. Journal of Clinical Oncology, 23(17), 3886-3896. https://doi.org/10.1200/JCO.2005.11.353

Epigenetic profiling of cutaneous T-cell lymphoma : Promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. / Van Doorn, Remco; Zoutman, Willem H.; Dijkman, Remco; De Menezes, Renee X.; Commandeur, Suzan; Mulder, Aat A.; Van Der Velden, Pieter A.; Vermeer, Maarten H.; Willemze, Rein; Yan, Pearlly S.; Huang, Hui-ming; Tensen, Cornelis P.

In: Journal of Clinical Oncology, Vol. 23, No. 17, 2005, p. 3886-3896.

Research output: Contribution to journalArticle

Van Doorn, R, Zoutman, WH, Dijkman, R, De Menezes, RX, Commandeur, S, Mulder, AA, Van Der Velden, PA, Vermeer, MH, Willemze, R, Yan, PS, Huang, H & Tensen, CP 2005, 'Epigenetic profiling of cutaneous T-cell lymphoma: Promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73', Journal of Clinical Oncology, vol. 23, no. 17, pp. 3886-3896. https://doi.org/10.1200/JCO.2005.11.353
Van Doorn, Remco ; Zoutman, Willem H. ; Dijkman, Remco ; De Menezes, Renee X. ; Commandeur, Suzan ; Mulder, Aat A. ; Van Der Velden, Pieter A. ; Vermeer, Maarten H. ; Willemze, Rein ; Yan, Pearlly S. ; Huang, Hui-ming ; Tensen, Cornelis P. / Epigenetic profiling of cutaneous T-cell lymphoma : Promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 17. pp. 3886-3896.
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abstract = "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.",
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T1 - Epigenetic profiling of cutaneous T-cell lymphoma

T2 - Promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73

AU - Van Doorn, Remco

AU - Zoutman, Willem H.

AU - Dijkman, Remco

AU - De Menezes, Renee X.

AU - Commandeur, Suzan

AU - Mulder, Aat A.

AU - Van Der Velden, Pieter A.

AU - Vermeer, Maarten H.

AU - Willemze, Rein

AU - Yan, Pearlly S.

AU - Huang, Hui-ming

AU - Tensen, Cornelis P.

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

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