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A specific DNA methylation profile correlates with a high risk of disease progression in stage I classical (Alibert‐Bazin type) mycosis fungoides
Author(s) -
Ferrara G.,
Pancione M.,
Votino C.,
Quaglino P.,
Tomasini C.,
Santucci M.,
Pimpinelli N.,
Cusano F.,
Sabatino L.,
Colantuoni V.
Publication year - 2014
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.12717
Subject(s) - dna methylation , mycosis fungoides , methylation , epigenetics , cancer research , biology , lymphoma , demethylating agent , bisulfite sequencing , oncology , pathology , immunology , medicine , genetics , gene , gene expression
Summary Background Mycosis fungoides ( MF ) is the most common type of cutaneous T ‐cell lymphoma; in its classical presentation it evolves slowly, but it can have an aggressive course in a subset of patients. Objectives To investigate the impact of epigenetic mechanisms on the progression of early stage MF . Methods We analysed DNA methylation at 12 different loci and long interspersed nucleotide elements‐1 ( LINE ‐1), as a surrogate marker of global methylation, on tissue samples from 41 patients with stage I MF followed up for at least 12 years or until disease progression. The methylation profiles were also analysed in two T ‐cell lymphoma cell lines and correlated with gene expression. Results The selected loci were methylated in a tumour‐specific manner; concomitant hypermethylation of at least four loci was more frequent in cases progressing within 1–3 and 3–6 years than in late‐progressive or non‐progressive cases. LINE ‐1 methylation was significantly lower in rapidly progressive MF at 3 years (61%, P < 0·001) than in those at 12 years (67%). PPARG , SOCS 1 and NEUROG 1 methylation showed remarkable differences among the prognostic groups, but only PPARG was a significant predictor of disease progression within 6 years, after adjustment for patients' age or gender. Strikingly, a methylation profile similar to progressive cases was found in highly proliferative Sézary‐derived HUT 78 cells but not in MF ‐derived HUT 102 cells. Exposure to a DNA demethylating agent restored sensitivity to apoptosis and cell cycle arrest. Conclusions Epigenetic silencing of specific biomarkers can predict the risk of disease progression in early‐stage MF , providing insights into its pathogenesis, prognosis and therapy.