Epigenomic Analysis of Sézary Syndrome Defines Patterns of Aberrant DNA Methylation and Identifies Diagnostic Markers.
Sézary syndrome (Sz) is a malignancy of skin-homing CD4(+) memory T cells that is clinically characterized by erythroderma, lymphadenopathy, and blood involvement. Distinction of Sz from erythroderma secondary to inflammatory skin diseases (erythrodermic inflammatory dermatosis [EID]) is often challenging. Recent studies identified recurrent mutations in epigenetic enzymes involved in DNA modification in Sz. Here we defined the DNA methylomes of purified CD4(+) T cells from patients with Sz, EID, and healthy control subjects. Sz showed extensive global DNA methylation alterations, with 7.8% of 473,921 interrogated autosomal CpG sites showing hypomethylation and 3.2% hypermethylation. Promoter CpG islands were markedly enriched for hypermethylation. The 126 genes with recurrent promoter hypermethylation in Sz included multiple candidate tumor suppressors that showed transcriptional repression, implicating aberrant methylation in the pathogenesis of Sz. Validation in an independent sample set showed promoter hypermethylation of CMTM2, C2orf40, G0S2, HSPB6, PROM1, and PAM in 94-100% of Sz samples but not in EID samples. Notably, promoter hypermethylation of a single gene, the chemokine-like factor CMTM2, was sufficient to accurately distinguish Sz from EID in all cases. This study shows that Sz is characterized by widespread yet distinct DNA methylation alterations, which can be used clinically as epigenetic diagnostic markers.
Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: rvandoorn@lumc.nl.
Remco
R
van Doorn
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Roderick C
RC
Slieker
Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
Stéphanie E
SE
Boonk
Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
Willem H
WH
Zoutman
Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
Jelle J
JJ
Goeman
Institut National de la Santé et de la Recherche Médicale U976, Onco-Dermatology, Immunology and Cutaneous Stem Cells, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Saint Louis Hospital, Department of Dermatology, Paris, France.
Martine
M
Bagot
Institut National de la Santé et de la Recherche Médicale U976, Onco-Dermatology, Immunology and Cutaneous Stem Cells, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Saint Louis Hospital, Department of Dermatology, Paris, France.
Laurence
L
Michel
Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
Cornelis P
CP
Tensen
Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
Rein
R
Willemze
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Bas T
BT
Heijmans
Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
Maarten H
MH
Vermeer
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics / Q000379:methods*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic / Q000235:genetics; D012751:Sezary Syndrome / Q000235:genetics* / Q000473:pathology*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*
D014408:Biomarkers, Tumor