Genome-Wide Analysis of Cutaneous T-Cell Lymphomas Identifies Three Clinically Relevant Classes

Abstract

This study was undertaken to identify recurrent genetic alterations of the three main types of cutaneous T-cell lymphomas (CTCLs): mycosis fungoides (MF), Sézary syndrome (SS), and cutaneous anaplastic large-cell lymphoma (CALCL). Using array-based comparative genomic hybridization, the molecular cytogenetic profiles of 72 samples obtained from 58 patients with CTCL corresponding to 24 transformed MF (T-MF), 16 SS, and 18 CALCLs were determined. T-MF was characterized by gains of 1q25-31, 7p22-11.2, 7q21, 7q31, and 17q12, and losses of 9p21, 10p11.2, and 10q26. SS exhibited gains of 8q23-24.3 and 17q23-24, as well as losses of 9p21, 10p12-11.2, 10q22-24, 10q25-26, and 17p13-q11.1. Finally, CALCL exhibited 6q27 and 13q34 losses. Such imbalances were statistically associated with one CTCL subtype. Unsupervised hierarchical clustering defined three categories of clinical relevance: (1) CALCL apart from epidermotropic-CTCL, (2) an SS-only category, and (3) a mixed category with T-MF and SS cases, with both primary and secondary SS cases. In rare cases, the genetic classification did not correspond to the inclusion diagnosis, possibly reflecting the association of two diseases in the same patient or initial misdiagnosis according to follow-up. Finally, different samples in the same patient clustered together, showing reproducibility of such a classifier.

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…This fundamental difference in the putative cell of origin between SS (T CM derived) and MF (T EM derived) is consistent with their distinct clinical behavior, as T CM may be found in both the peripheral blood, lymph node and skin and are long-lived cells resistant to apoptosis, while skin-resident T EM cells fail to circulate in peripheral blood, remaining fixed within the skin [18]. The contention that MF and SS originate from different T-cell subsets is consistent with comparative genomic hybridization (CGH) and gene-expression profiling data demonstrating that these CTCL subtypes are genetically distinct [19,20].…”

“…Patients with advanced-stage MF/SS require a multidisciplinary approach, as various combinations of skin-directed therapies, biologic-response modifiers and ultimately the [19,20,197] 17p 9-71 TP53 (p13.1) [19,20,197] *Associated with inferior overall survival.…”

“…Therefore, when these patients were omitted from analysis, the loss of 9p21 was associated with decreased overall survival that approached, but did not reach, statistical significance [93]. Despite this, the adverse prognostic significance of 9p21 loss is supported by multiple patient cohorts including both MF and SS [19,20,197]. Additional cytogenetic abnormalities, involving gains of chromosomes 1q and 8q and losses of chromosome 10q, have been associated with inferior survival and are summarized in Table V.…”

Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides

“…However, MF can have chromosomal gains and losses, with the most common being gains within chromosome 7 and losses within chromosomes 1, 10, and 17. [10][11][12] It is unclear whether any of the alterations reported have a role in the development of MF. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, integral to interleukin-2 (IL-2) signaling and cellular proliferation, can be deregulated in MF and CTCL, including increased and constitutive phosphorylation of STAT3 and STAT5.…”

MicroRNA-mediated Gene Expression in Sezary Syndrome: An Overview

“…The management approach is truly multidisciplinary [14]; the various treatment options are outlined in Table 1. High throughput analyses have been recently performed on whole genome, gene expression and microRNA profiles to understand the molecular process implicated in the etiopathogenesis of SS [15] [16][17] [18]. In the past few decades, both conventional and molecular cytogenetics study have been used to analyze the pathogenesis and prognosis of Sezary syndrome.…”