title: CDKN2A-CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma.
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.
authors.affiliation: EA 2406 Histology and Molecular Pathology, University of Bordeaux, Bordeaux, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Laharanne
authors.forename: Edith
authors.initials: E
authors.lastname: Chevret
authors.forename: Yamina
authors.initials: Y
authors.lastname: Idrissi
authors.forename: Catherine
authors.initials: C
authors.lastname: Gentil
authors.forename: Michel
authors.initials: M
authors.lastname: Longy
authors.forename: Jackie
authors.initials: J
authors.lastname: Ferrer
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.forename: Thomas
authors.initials: T
authors.lastname: Jouary
authors.forename: Béatrice
authors.initials: B
authors.lastname: Vergier
authors.forename: Marie
authors.initials: M
authors.lastname: Beylot-Barry
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Merlio
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D055028:Comparative Genomic Hybridization; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D017353:Gene Deletion; D019942:Genes, p16; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D025803:Tumor Suppressor Protein p14ARF