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

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

doi:10.1200/jco.2005.11.353

Cited by 214 publications

(161 citation statements)

References 44 publications

Supporting

Mentioning

153

Contrasting

Unclassified

Order By: Relevance

“…52 Epigenetic profiling already showed p15 INK4B promoter methylation in about 10% of CTCL cases. 53 Methylation of CDKN2A-CDKN2B gene promoters was not specifically observed in our epidermotropic CTCL cases with deletion, and cases with homozygous deletion (cases 6 and 7) also exhibited p15 INK4B promoter methylation that could be carried by non-tumor cells. The absence of CDKN2A-CDKN2B locus epigenetic global silencing does not support the use of demethylating agents in clinical trials of CTCL.…”

Section: Discussionmentioning

confidence: 55%

CDKN2A–CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma

et al. 2010

View full text Add to dashboard Cite

Inactivation of the CDKN2A-CDKN2B locus has been reported in the most frequent subtypes of cutaneous T-cell lymphomas (CTCLs), mycosis fungoides, Sé zary syndrome (SS) and CD30 þ cutaneous anaplastic large cell lymphoma. To investigate whether genetic or epigenetic inactivation of CDKN2A-CDKN2B is more specifically observed in certain CTCL subtypes with clinical impact, we used array-comparative genomic hybridization, quantitative PCR, interphase fluorescent in situ hybridization and methylation analyses of p14 ARF p16 INK4A and p15 INK4B promoters. We studied 67 samples from 58 patients with either transformed mycosis fungoides (n ¼ 24), SS (n ¼ 16) or CD30 þ cutaneous anaplastic large cell lymphoma (n ¼ 18). We observed combined CDKN2A-CDKN2B deletion in both transformed mycosis fungoides (n ¼ 17, 71%) and SS patients (n ¼ 7, 44%), but, surprisingly, in only one CD30 þ cutaneous anaplastic large cell lymphoma case. Interphase fluorescent in situ hybridization showed 9p21 loss in 17 out of 19 cases, with 9p21 deletion indicating either hemizygous (n ¼ 4) or homozygous (n ¼ 2) deletion, with mixed patterns in most patients (n ¼ 11). The limited size of 9p21 deletion was found to account for false-negative detection by either BAC arrays (n ¼ 9) or fluorescent in situ hybridization (n ¼ 2), especially in patients with Sé zary syndrome (n ¼ 6). Methylation was found to be restricted to the p15 INK4B gene promoter in patients with or without 9p21 deletion and did not correlate with prognosis. In contrast, CDKN2A-CDKN2B genetic loss was strongly associated with a shorter survival in CTCL patients (P ¼ 0.002) and more specifically at 24 months in transformed mycosis fungoides and SS patients (P ¼ 0.02). As immunohistochemistry for p16 INK4A protein was not found to be informative, the genetic status of the CDKN2A-CDKN2B locus would be relevant in assessing patients with epidermotropic CTCLs in order to identify those cases where the disease was more aggressive. Keywords: array-based comparative genomic hybridization; cutaneous T-cell lymphoma; CDKN2A-CDKN2B; mycosis fungoides; Sé zary syndrome; 9p21 deletionThe cell cycle, and especially G1-S progression, is controlled by the p14 ARF -mdm2-p53 and p16 INK4A / p15 INK4B -Rb1 pathways (reviewed by Sharpless and DePinho 1 ). Both p16 INK4A and p15 INK4B proteins are able to induce cell-cycle arrest in the G1 phase by inhibiting the cyclin-dependent kinases CDK4-and CDK6-mediated phosphorylation of the retinoblastoma protein that is required for cell-cycle progression (reviewed by Barbacid et al 2 and Ortega et al 3 ). The p14 ARF protein mainly acts on the MDM2-p53 pathway, inducing either cell cycle arrest or apoptosis (reviewed by Sherr et al 4 and Gil and Peters 5 ).Interestingly, the p14 ARF , p16 INK4A and p15 INK4B proteins are encoded by the same CDKN2A-CDKN2B locus on the chromosomal band 9p21:

show abstract

Section: Discussionmentioning

confidence: 55%

CDKN2A–CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma

et al. 2010

View full text Add to dashboard Cite

show abstract

“…A number of mechanisms, including promoter methylation [86][87][88], gene mutations [89] and loss of the long arm of chromosome 10 [90] result in diminished Fas expression in CTCL and reduced sensitivity to apoptosis. In addition, promoter methylation and epigenetic instability leading to the inactivation of many tumor suppressor genes, including those involved in the induction of apoptosis, appear to be commonly used mechanisms of lymphomagenesis in CTCL [91].…”

Section: Immunopathogenesismentioning

confidence: 99%

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

Wilcox

2011

American J Hematol

View full text Add to dashboard Cite

Disease overview: Cutaneous T‐cell lymphomas are a heterogenous group of T‐cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS).Diagnosis: The diagnosis of MF or SS requires the integration of clinical and histopathologic data.Risk‐adapted therapy: Tumor, node, metastasis, and blood (TNMB) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin‐directed therapies is preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic‐response modifiers, denileukin diftitox, and histone deacetylase inhibitors before escalating therapy to include systemic, single‐agent chemotherapy. Multiagent chemotherapy may be used for those patients with extensive visceral involvement requiring rapid disease control. In highly‐selected patients with disease refractory to standard treatments, allogeneic stem‐cell transplantation may be considered. Am. J. Hematol., 2011. © 2011 Wiley‐Liss, Inc.

show abstract

“…[39][40][41] Transcriptional downregulation was shown to be associated with PTPRG promoter methylation in the cutaneous T-cell lymphomas study. 39 This study used a similar microarray for identification of differential methylation as the present study. We did not find differential methylation of the PTPRG promoter region between normal and colon tumour samples on the microarray.…”

Section: Discussionmentioning

confidence: 89%

Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer

et al. 2010

View full text Add to dashboard Cite

DNA methylation is a hallmark in a subset of right-sided colorectal cancers. Methylation-based screening may improve prevention and survival rate for this type of cancer, which is often clinically asymptomatic in the early stages. We aimed to discover prognostic or diagnostic biomarkers for colon cancer by comparing DNA methylation profiles of right-sided colon tumours and paired normal colon mucosa using an 8.5 k CpG island microarray. We identified a diagnostic CpG-rich region, located in the first intron of the protein-tyrosine phosphatase gamma gene (PTPRG) gene, with altered methylation already in the adenoma stage, that is, before the carcinoma transition. Validation of this region in an additional cohort of 103 sporadic colorectal tumours and 58 paired normal mucosa tissue samples showed 94% sensitivity and 96% specificity. Interestingly, comparable results were obtained when screening a cohort of Lynch syndrome-associated cancers. Functional studies showed that PTPRG intron 1 methylation did not directly affect PTPRG expression, however, the methylated region overlapped with a binding site of the insulator protein CTCF. Chromatin immunoprecipitation (ChIP) showed that methylation of the locus was associated with absence of CTCF binding. Methylation-associated changes in CTCF binding to PTPRG intron 1 could have implications on tumour gene expression by enhancer blocking, chromosome loop formation or abrogation of its insulator function. The high sensitivity and specificity for the PTPRG intron 1 methylation in both sporadic and hereditary colon cancers support biomarker potential for early detection of colon cancer.

show abstract

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

Cited by 214 publications

References 44 publications

CDKN2A–CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma

CDKN2A–CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer

Contact Info

Product

Resources

About