Epigenomic Analysis of Sézary Syndrome Defines Patterns of Aberrant DNA Methylation and Identifies Diagnostic Markers

Abstract

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.

Molecular pathogenesis of cutaneous lymphomas

“…These include several tumor suppressor genes as CDKN2A and Fas. The result further indicates that measuring promoter methylation of a singular gene, CMTM2 (chemokine‐like factor gene), is sufficient to distinguish Sézary syndrome from benign conditions . Besides complex molecular methods, it has been shown by Boonk et al that strong expression of Tox and PD1 is also well evaluable in the diagnosis of Sézary syndrome …”

Malignant inflammation in cutaneous T‐cell lymphoma—a hostile takeover

“…Although it is not known exactly how the malignant T cells gain the capacity to impose these changes on the inflammatory environment, a series of recent data suggests that endogenous changes in the malignant T cells, including somatic mutations, somatic copy number variations, and epigenetic deregulation, may play a critical role [19–25, 60, 151, 152]. Exogenous factors such as bacterial colonization and infection may also drive activation of pro-oncogenic mechanisms and inhibit anti-tumor immunity.…”

CCL21 Induces mTOR-dependent MALAT1 Expression, Leading to Cell Migration in Cutaneous T-Cell Lymphoma

“…Microarray data from tumorous MF tissue indicated that miR-34a is a candidate oncogenic molecule and miR-29a acts as a tumor suppressor, highlighting their regulatory role in the progression of MF (14). DNA methylation analysis has shown that Sézary syndrome is characterized by widespread yet distinct DNA methylation alterations, and that promoter hypermethylation of a single gene, chemokine-like factor chemokine-like factor-like MARVEL transmembrane domain containing 2 (CMTM2), was sufficient to accurately distinguish it from other erythrodermic inflammatory diseases (15). Together this evidence suggests epigenetic regulation may play a significant role on the pathogenesis and progression of MF.…”