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CDKN2A-CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma
Elodie Laharanne1, Edith Chevret, Yamina Idrissi
1EA 2406 Histology and Molecular Pathology, University of Bordeaux, Bordeaux, France.
Abstract:
Inactivation of the CDKN2A-CDKN2B locus has been reported in the most frequent subtypes of cutaneous T-cell lymphomas (CTCLs), mycosis fungoides, Sézary syndrome (SS) and CD30+ 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=24), SS (n=16) or CD30+ cutaneous anaplastic large cell lymphoma (n=18). We observed combined CDKN2A-CDKN2B deletion in both transformed mycosis fungoides (n=17, 71%) and SS patients (n=7, 44%), but, surprisingly, in only one CD30+ 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=4) or homozygous (n=2) deletion, with mixed patterns in most patients (n=11). The limited size of 9p21 deletion was found to account for false-negative detection by either BAC arrays (n=9) or fluorescent in situ hybridization (n=2), especially in patients with Sézary syndrome (n=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=0.002) and more specifically at 24 months in transformed mycosis fungoides and SS patients (P=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.
Insights
Genetic loss of the CDKN2A-CDKN2B locus is common in mycosis fungoides and Sézary syndrome, indicating a poorer prognosis for cutaneous T-cell lymphoma patients. This genetic alteration, not methylation, is linked to shorter survival.
Area of Science:
- Oncology
- Genetics
- Dermatology
Background:
- The CDKN2A-CDKN2B locus is frequently inactivated in cutaneous T-cell lymphomas (CTCLs).
- Understanding the mechanisms (genetic vs. epigenetic) and clinical impact of this inactivation is crucial for specific CTCL subtypes.
Purpose of the Study:
- To investigate the specific roles of genetic deletion and promoter methylation of CDKN2A-CDKN2B in CTCL subtypes.
- To determine the clinical impact of CDKN2A-CDKN2B inactivation on patient survival.
Main Methods:
- Array-comparative genomic hybridization (aCGH), quantitative PCR, and interphase fluorescent in situ hybridization (iFISH) were used to detect genetic alterations.
- Methylation analyses of p14ARF, p16INK4A, and p15INK4B promoters were performed.
- 67 samples from patients with transformed mycosis fungoides, Sézary syndrome, and CD30+ cutaneous anaplastic large cell lymphoma were studied.
Main Results:
- Combined CDKN2A-CDKN2B deletion was observed in 71% of transformed mycosis fungoides and 44% of Sézary syndrome cases, but rarely in CD30+ cutaneous anaplastic large cell lymphoma.
- 9p21 loss was detected by iFISH in most cases, with varying patterns of hemizygous, homozygous, or mixed deletions.
- Methylation was limited to the p15INK4B promoter and did not correlate with prognosis.
- CDKN2A-CDKN2B genetic loss significantly correlated with shorter survival in CTCL patients (P=0.002), particularly at 24 months in transformed mycosis fungoides and Sézary syndrome (P=0.02).
Conclusions:
- Genetic loss of the CDKN2A-CDKN2B locus is a significant prognostic marker in transformed mycosis fungoides and Sézary syndrome.
- Assessing the genetic status of CDKN2A-CDKN2B is valuable for identifying aggressive epidermotropic CTCLs.
- Immunohistochemistry for p16INK4A protein was not informative for predicting prognosis.
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