A Meta-Analysis of Gene Expression Data Identifies a Molecular Signature Characteristic for Tumor-Stage Mycosis Fungoides

Abstract

Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma (CTCL). To identify a molecular signature characteristic of MF tumor stage, we used a bioinformatic approach involving meta-analysis of publicly available gene expression data sets combined with previously generated gene expression data. Results for a selection of genes were further refined and validated by quantitative PCR and inclusion of additional controls. With this approach, we identified a profile specific for MF tumor stage, consisting of 989 aberrantly expressed genes, the majority of which (718 genes) are statistically significantly more expressed in MF compared with normal skin, inflamed skin, and normal T cells. As expected, the signature contains genes reflecting the highly proliferative characteristic of this T-cell malignancy, including altered expression of cell cycle and kinetochore regulators. We uncovered details of the immunophenotype, suggesting that MF originates from IL-32-producing cells and identified previously unreported therapeutic targets and/or diagnostic markers, for example, GTSF1 and TRIP13. Loss of expression of the NF-κB inhibitor, NFKBIZ, may partly explain the enhanced activity of NF-κB, which is a hallmark of MF and other CTCLs.

Analysis of STAT4 expression in cutaneous T-cell lymphoma (CTCL) patients and patient-derived cell lines

“…7 Multiple studies attempted to clarify the genetic multistep carcinogenesis of CTCL. [8][9][10][11] Persistent activation of transcription factors of the signal transducers and activators of transcription (STAT) protein family has been implicated in the pathogenesis of a wide variety of human cancers, including CTCL. Expression and function of STAT3, STAT4 and STAT5 have been extensively studied in CTCL and these genes appear to play an important role in the disease pathogenesis and can be used as important prognostic markers.…”

Ectopic expression of embryonic stem cell and other developmental genes in cutaneous T-cell lymphoma

“…2 Multiple studies attempted to clarify the genetic multistep carcinogenesis of CTCL. [3][4][5][6] In addition, several studies identified recurrent chromosomal aberrations in MF/SS. [7][8][9][10][11][12] While much research is focused on investigation of known oncogenes and tumor suppressor genes in CTCL, 6,[13][14][15] recent reports suggest that it is also important to look for genes that could be erroneously expressed in this cancer.…”

GTSF1 gene may serve as a novel potential diagnostic biomarker for liver cancer

“…Therefore, multiple genetic and epigenetic factors may affect HCC development (13). It has previously been reported in several studies that the GTSF1 gene participates in DNA methylation and retrotransposon activation in germ cells, particularly in cell proliferation, and that it is present in MF tumor samples, suggesting that it may serve a role in the apoptosis resistance of MF (7,9,14). Therefore, it may be concluded that the GTSF1 gene may serve a role as a proliferation factor during various physiological processes, including growth, development, differentiation and reproduction in animals and plants.…”

“…It has been suggested that the expression pattern of GTSF1 and its high conservation may serve an important role in germ cell development (8). A meta-analysis of gene expression data suggested that, as male GTSF1-knockout mice are sterile owing to a large proportion of dead germ cells, aberrant overexpression of GTSF1 may have a role in the apoptosis resistance of Mycosis Fungoides (MF) (9). In the present study, screening of gene expression in liver cancer samples, all histologically HCC, revealed an association between GTSF1 expression and liver cancer cell proliferation and apoptosis.…”