Frequent Abnormalities of the P15 and P16 Genes in Mycosis Fungoides and Sezary Syndrome

Scarisbrick, Julia; Woolford, Alison J.-A.; Calonje, Eduardo; Φωτίου, Α.; Ferreira, S.V.; Orchard, Guy; Russell‐Jones, Robin; Whittaker, Sean

doi:10.1046/j.0022-202x.2001.01682.x

Cited by 115 publications

(79 citation statements)

References 54 publications

(69 reference statements)

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“…Therefore, combined deletion of CDKN2A/CDKN2B or their epigenetic silencing, leads to RB1 phosphorylation and loss of p53, culminating in cell-cycle progression. These abnormalities are frequently observed in CTCL, suggesting their early involvement in disease pathogenesis [92,93]. Cyclin upregulation, including cyclinD1, and loss of RB1 have also been described [94].…”

Section: Immunopathogenesismentioning

confidence: 92%

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

Wilcox

2011

American J Hematol

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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.

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Section: Immunopathogenesismentioning

confidence: 92%

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

Wilcox

2011

American J Hematol

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“…22 Interestingly, no point mutation of either p16 INK4A or p15 INK4B genes was found, but aberrant 5 0 -CpG island methylation of either p16 INK4A and/or p15 INK4B , but not of p14 ARF , was detected. [21][22][23] In SS, selective hypermethylation of p15 INK4B but not p14 ARF or p16 INK4A was observed in 42% of cases, 21,24 a pattern not seen in aggressive mycosis fungoides. 22 Using enrichment in tumor cells by microdissection of 25 skin samples, LOH was similarly observed in two out of 15 plaque-stage mycosis fungoides and in two out of 10 tumor-stage mycosis fungoides.…”

Section: And Gil and Peters 5 )mentioning

confidence: 95%

“…Using microsatellite markers surrounding the CDKN2A-CDKN2B locus, loss of heterozygosity (LOH), suggesting either hemizygous or homozygous deletion, was indeed detected equally in the early and late stages of mycosis fungoides (21%) and SS (37%) cases (25% of epidermotropic CTCL). 21 Another group suggested that LOH or homozygous deletion was not present in patients with early-stage and stable mycosis fungoides (n ¼ 21), but appeared during the tumoral progression of mycosis fungoides (3 out of 11 samples). 22 Interestingly, no point mutation of either p16 INK4A or p15 INK4B genes was found, but aberrant 5 0 -CpG island methylation of either p16 INK4A and/or p15 INK4B , but not of p14 ARF , was detected.…”

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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“…[15][16][17][18][19] However, our findings suggest that p16 gene methylation is not associated with the tumor progression but rather may contribute to the 35,36 and by the frequent p16 gene methylation found in monoclonal gammopathy of undetermined significance, in the plaque phase of mycosis fungoides, and in other premalignant lesions. [20][21][22]37 Several MALT lymphoma-specific or -associated gene alterations have been reported, such as translocations between the immunoglobulin heavy chain gene and BCL10 gene or MALT1 gene, trisomy 3, and trisomy 18, as well as API2-MALT1 fusion. 38 These seem to be mutually exclusive, and constitute up to 80% of the pulmonary MALT lymphoma cases.…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17][18][19] However, it has also been suggested that the methylation of this gene is one of the early events in the development of lymphoid malignancies. [20][21][22] MALT lymphoma constitutes more than 80% of all primary lung lymphomas. 23 It should be noted that the involvement of API2-MALT1 fusion is particularly high (up to half of all cases) in pulmonary MALT lymphoma compared with MALT lymphomas at other sites, 24 and may define a distinctive clinicopathologic subgroup of pulmonary MALT lymphomas.…”

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confidence: 99%

p16/INK4a gene methylation is a frequent finding in pulmonary MALT lymphomas at diagnosis

Takino

Okabe

et al. 2005

Modern Pathology

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p16/INK4a gene alterations have been associated with tumor progression in lymphoid malignancies. However, their significance in mucosa-associated lymphoid tissue (MALT) lymphoma is unclear. We investigated p16 gene methylation and mutation in a large series of untreated cases of pulmonary MALT lymphoma and diffuse large B-cell lymphoma (DLBL), and correlated p16 gene alterations with a MALT lymphoma-specific API2-MALT1 fusion and the clinicopathologic features of MALT lymphoma. The API2-MALT1 fusion was detected by multiplex reverse transcription polymerase chain reaction in 25/60 (42%) cases of MALT lymphoma, but none of 11 DLBLs. Methylation-sensitive single-strand conformation analysis showed that p16 gene methylation was frequently detected in 36/60 (60%) cases of MALT lymphoma. The gene was similarly methylated in DLBL cases (6/11, 55%). A p16 gene mutation was found in one (p16 gene-methylation) of 44 MALT lymphomas and in none of six diffuse large B-cell lymphomas. Statistical analysis showed that the p16 gene methylation status did not correlate with API2-MALT1 fusion or any of the clinicopathologic factors including serum LDH, clinical stage, and increased large cells. These findings suggest that p16 methylation is not associated with tumor progression, but may be an early event in MALT lymphomagenesis that might be maintained through the progression of the tumor.

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Frequent Abnormalities of the P15 and P16 Genes in Mycosis Fungoides and Sezary Syndrome

Cited by 115 publications

References 54 publications

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

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

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

p16/INK4a gene methylation is a frequent finding in pulmonary MALT lymphomas at diagnosis

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