1216 Commentaries
Mycosis fungoides: promoter hypermethylation predicts disease progression DOI: 10.1111/bjd.12870 ORIGINAL ARTICLE, p 1266 The development and progression of malignant diseases is driven by the acquisition of not only genetic, but also epigenetic alterations. The term epigenetics has been used to describe heritable changes in gene expression resulting from changes in chromatin structure without alterations in the primary DNA sequence. DNA methylation is the most studied epigenetic mechanism and refers to the addition of a methyl group to a cytosine nucleotide occurring in a CG dinucleotide. Approximately half of human gene promoters contain so-called CpG islands, genomic regions with high CG dinucleotide density, which are usually unmethylated. However, in cancer cells dozens to hundreds of promoter CpG islands become aberrantly methylated, which is often associated with transcriptional silencing of affected genes. Promoter CpG island hypermethylation demonstrates tumour-type-specific patterns and can contribute to the malignant phenotype of cells by inactivating tumour suppressor genes. Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and is known to have a highly variable disease course. Whereas most patients who present with erythematous plaques have stable disease for years, a subset of patients experiences rapid disease progression with development of skin tumours and extracutaneous dissemination of tumour cells. Several tumour suppressor genes have previously been found to be silenced through promoter hypermethylation in MF, including CDKN2A, BCL7A and MLH1, pointing to the relevance of epigenetic mechanisms in its pathogenesis.1–3 In a study published in this issue of BJD, Gerardo Ferrara and colleagues examined the occurrence of promoter hypermethylation of 12 selected genes in early-stage MF skin lesions.4 Frequent hypermethylation of several genes such as CDKN1B and IGF2 was noted. Remarkably, the frequency of promoter hypermethylation of this gene panel was observed to be higher in patients with early-stage lesions who would go on to experience disease progression than in patients with a stable disease course. The authors found that in particular promoter hypermethylation of the peroxisome proliferatoractivated receptor-c gene (PPARG) in early-stage MF skin lesions was predictive of disease progression. The PPARG gene encodes a nuclear receptor regulating lipid metabolism that is normally expressed by T lymphocytes.5 Promoter hypermethylation of this potential tumour suppressor gene was associated with transcriptional repression. This study demonstrates that the frequency and pattern of promoter hypermethylation is associated with the propensity of MF to progress. The prognostic significance of promoter hypermethylation of PPARG and other genes might be applied British Journal of Dermatology (2014) 170, pp1214–1218
in the clinic. In addition, this study supports the notion that epigenetic deregulation acts as a driving force in MF, which is in line with the efficacy of epigenetic drugs such as the histone deacetylase inhibitor vorinostat in this T-cell malignancy. If epigenetic inactivation of PPARG might have a causal role in disease progression, then pharmacological agonists of the protein might have a therapeutic effect by limiting MF aggressiveness.6 This study clearly shows the clinical potential of detecting epigenetic alterations in MF. We can expect that future genome-wide analysis of DNA methylation in MF will reveal more diagnostic and prognostic biomarkers, which should be confirmed in large patient cohorts. Conflicts of interest None declared.
Department of Dermatology, Leiden University Medical Center, Albinusdreef 2, 2300, RC Leiden, the Netherlands E-mail: [email protected]
R.
VAN
DOORN
References 1 Navas IC, Ortiz-Romero PL, Villuendas R et al. p16(INK4a) gene alterations are frequent in lesions of mycosis fungoides. Am J Pathol 2000; 156:1565–72. 2 Scarisbrick JJ, Mitchell TJ, Calonje E et al. Microsatellite instability is associated with hypermethylation of the hMLH1 gene and reduced gene expression in mycosis fungoides. J Invest Dermatol 2003; 121:894–901. 3 van Doorn R, Zoutman WH, Dijkman R et al. Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol 2005; 23:3886–96. 4 Ferrara G, Pancione M, Votine C et al. A specific DNA methylation profile correlates with a high risk of disease progression in stage I classical (Alibert–Bazin type) mycosis fungoides. Br J Dermatol 2014 170:1266–75. 5 Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2002; 2:748–59. 6 Zhang C, Ni X, Konopleva M et al. The novel synthetic oleanane triterpenoid CDDO (2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid) induces apoptosis in mycosis fungoides/Sezary syndrome cells. J Invest Dermatol 2004; 123:380–7.
Mortality of bullous pemphigoid in Asia: the same as in Europe? DOI: 10.1111/bjd.13016 ORIGINAL ARTICLE, p 1319 Bullous pemphigoid (BP) is the most common autoimmune blistering disease of the skin, usually affecting the elderly. It is © 2014 British Association of Dermatologists
Mycosis fungoides: promoter hypermethylation predicts disease progression DOI: 10.1111/bjd.12870 ORIGINAL ARTICLE, p 1266 The development and progression of malignant diseases is driven by the acquisition of not only genetic, but also epigenetic alterations. The term epigenetics has been used to describe heritable changes in gene expression resulting from changes in chromatin structure without alterations in the primary DNA sequence. DNA methylation is the most studied epigenetic mechanism and refers to the addition of a methyl group to a cytosine nucleotide occurring in a CG dinucleotide. Approximately half of human gene promoters contain so-called CpG islands, genomic regions with high CG dinucleotide density, which are usually unmethylated. However, in cancer cells dozens to hundreds of promoter CpG islands become aberrantly methylated, which is often associated with transcriptional silencing of affected genes. Promoter CpG island hypermethylation demonstrates tumour-type-specific patterns and can contribute to the malignant phenotype of cells by inactivating tumour suppressor genes. Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and is known to have a highly variable disease course. Whereas most patients who present with erythematous plaques have stable disease for years, a subset of patients experiences rapid disease progression with development of skin tumours and extracutaneous dissemination of tumour cells. Several tumour suppressor genes have previously been found to be silenced through promoter hypermethylation in MF, including CDKN2A, BCL7A and MLH1, pointing to the relevance of epigenetic mechanisms in its pathogenesis.1–3 In a study published in this issue of BJD, Gerardo Ferrara and colleagues examined the occurrence of promoter hypermethylation of 12 selected genes in early-stage MF skin lesions.4 Frequent hypermethylation of several genes such as CDKN1B and IGF2 was noted. Remarkably, the frequency of promoter hypermethylation of this gene panel was observed to be higher in patients with early-stage lesions who would go on to experience disease progression than in patients with a stable disease course. The authors found that in particular promoter hypermethylation of the peroxisome proliferatoractivated receptor-c gene (PPARG) in early-stage MF skin lesions was predictive of disease progression. The PPARG gene encodes a nuclear receptor regulating lipid metabolism that is normally expressed by T lymphocytes.5 Promoter hypermethylation of this potential tumour suppressor gene was associated with transcriptional repression. This study demonstrates that the frequency and pattern of promoter hypermethylation is associated with the propensity of MF to progress. The prognostic significance of promoter hypermethylation of PPARG and other genes might be applied British Journal of Dermatology (2014) 170, pp1214–1218
in the clinic. In addition, this study supports the notion that epigenetic deregulation acts as a driving force in MF, which is in line with the efficacy of epigenetic drugs such as the histone deacetylase inhibitor vorinostat in this T-cell malignancy. If epigenetic inactivation of PPARG might have a causal role in disease progression, then pharmacological agonists of the protein might have a therapeutic effect by limiting MF aggressiveness.6 This study clearly shows the clinical potential of detecting epigenetic alterations in MF. We can expect that future genome-wide analysis of DNA methylation in MF will reveal more diagnostic and prognostic biomarkers, which should be confirmed in large patient cohorts. Conflicts of interest None declared.
Department of Dermatology, Leiden University Medical Center, Albinusdreef 2, 2300, RC Leiden, the Netherlands E-mail: [email protected]
R.
VAN
DOORN
References 1 Navas IC, Ortiz-Romero PL, Villuendas R et al. p16(INK4a) gene alterations are frequent in lesions of mycosis fungoides. Am J Pathol 2000; 156:1565–72. 2 Scarisbrick JJ, Mitchell TJ, Calonje E et al. Microsatellite instability is associated with hypermethylation of the hMLH1 gene and reduced gene expression in mycosis fungoides. J Invest Dermatol 2003; 121:894–901. 3 van Doorn R, Zoutman WH, Dijkman R et al. Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol 2005; 23:3886–96. 4 Ferrara G, Pancione M, Votine C et al. A specific DNA methylation profile correlates with a high risk of disease progression in stage I classical (Alibert–Bazin type) mycosis fungoides. Br J Dermatol 2014 170:1266–75. 5 Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2002; 2:748–59. 6 Zhang C, Ni X, Konopleva M et al. The novel synthetic oleanane triterpenoid CDDO (2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid) induces apoptosis in mycosis fungoides/Sezary syndrome cells. J Invest Dermatol 2004; 123:380–7.
Mortality of bullous pemphigoid in Asia: the same as in Europe? DOI: 10.1111/bjd.13016 ORIGINAL ARTICLE, p 1319 Bullous pemphigoid (BP) is the most common autoimmune blistering disease of the skin, usually affecting the elderly. It is © 2014 British Association of Dermatologists
