Molecular cytogenetic analysis of cutaneous T-cell lymphomas: identification of common genetic alterations in Sezary syndrome and mycosis fungoides

Mao, Xin; Lillington, Debra M.; Scarisbrick, Julia; Mitchell, Tracey; Czepulkowski, Barbara; Russell‐Jones, Robin; Young, Bryan D.; Whittaker, Sean

doi:10.1046/j.1365-2133.2002.04966.x

Cited by 148 publications

(149 citation statements)

References 44 publications

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“…27 Nor did comparative genomic hybridization studies of both mycosis fungoides and SS cases find 9p21 loss as a recurrent imbalance of these lymphomas. 28,29 However, recent array-comparative genomic hybridization data obtained by the Leiden University group identified 9p21 loss in 41% of patients, with mycosis fungoides associated with lower survival rate. 30,31 By comparison, the deletion was not found in patients with SS.…”

Section: And Gil and Peters 5 )mentioning

confidence: 99%

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

et al. 2010

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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:

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Section: And Gil and Peters 5 )mentioning

confidence: 99%

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

et al. 2010

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“…86,87 Several studies have identified a consistent pattern of identical chromosomal abnormalities in SS, which was almost identical to that in MF, suggesting that both conditions represent parts of the same spectrum of disease with a similar pathogenesis. 88,89 Chromosomal amplification of the JUNB gene, a member of the activator protein-1 (AP-1) transcription factor complex involved in cell proliferation and T helper 2 (Th2) cytokine expression by T cells, has been identified in SS. 90,91 Prognosis and predictive factors.…”

Section: Sé Zary Syndromementioning

confidence: 99%

WHO-EORTC classification for cutaneous lymphomas

Willemze

Jaffe

Burg

et al. 2005

Blood

3,520

4,355

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“…However, disease progression in MF/SS has been associated with several genetic abnormalities that enable a dominant clonal population to emerge. Chromosomal rearrangement hot spots have been detected in MF/SS and include deletions on 1p, 17p, 10q, and 19 and gains at 4q, 18, and 17q (26). Early patch and plaque MF lesions may demonstrate defects in Fas expression or constitutive STAT activation that result in impaired tumor cell apoptosis (27,28).…”

Section: Malignant T Cell Clonality: a New Diagnostic Tool For Mf/ssmentioning

confidence: 99%

Immunopathogenesis and therapy of cutaneous T cell lymphoma

Kim¹

2005

Journal of Clinical Investigation

190

157

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Molecular cytogenetic analysis of cutaneous T-cell lymphomas: identification of common genetic alterations in Sezary syndrome and mycosis fungoides

Abstract: These findings provide a comprehensive assessment of genetic abnormalities in CTCL and a rational approach for further studies.

Cited by 148 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

WHO-EORTC classification for cutaneous lymphomas

Immunopathogenesis and therapy of cutaneous T cell lymphoma

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