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Ectopic expression of cancer-testis antigens in cutaneous T-cell lymphoma patients

Significance Statement

Cutaneous T-Cell Lymphoma (CTCL) is a rare, but potentially devastating malignancy. It represents a heterogeneous group of Non-Hodgkin’s lymphomas that are characterized by localization of malignant T lymphocytes to the skin. While much research is focused on investigation of known oncogenes and tumor suppressor genes in Cutaneous T-Cell Lymphoma , recent reports suggest that it is also important to look for genes that could be ectopically expressed in this cancer1, 2. Our recent work demonstrated that cancer testis (CT) genes are ectopically expressed in this malignancy1. These genes are normally present solely in testicular germ cells and can be ectopically expressed in a variety of cancers. We and others have suggested that CT antigens during carcinogenesis may play an important role in maintaining cell survival (i.e., inhibition of apoptosis), promoting resistance to various forms of chemo- and radio-therapy and contributing to oncogenesis by targeting p53 and p21 tumor suppressor genes. Also, since SYCP1 (Synaptonemal Complex Protein 1), SYCP3, DMC1 (Disrupted Meiotic cDNA 1) and REC8 CT antigens under normal conditions regulate generation of double strand DNA breaks during crossing over in meiosis, it was suggested that these genes may promote aneuploidy and genomic instability in cancers by producing aberrant chromosomal translocations. Furthermore, recently we investigated the expression of Embryonic Stem Cell (ESC) genes in CTCL2. Many of these genes are involved in the maintenance of pluripotency of embryonic stem cells and their aberrant re-expression in Cutaneous T-Cell Lymphoma may be promoting cancer stem cell-like phenotype in this malignancy.  This study2 for the first time demonstrated the expression of ESC genes in Cutaneous T-Cell Lymphoma lesional skin biopsies and patient-derived cell lines. Our results highlight that OCT4, EED, TCF3, THAP11, CHD7, TIP60 and TRIM28 ESC genes are preferentially expressed in Cutaneous T-Cell Lymphoma , but not in benign inflammatory dermatoses that often mimic this malignancy. Finally, recent studies highlighted that malignant T cells in Cutaneous T-Cell Lymphoma are able to express few B cell-specific genes, one of which is the Src kinase BLK, a bona fide oncogene. In addition, recent translational experimental work revealed that TOX expression, which is usually silenced in mature T cells, can be used as a robust prognostic and diagnostic marker for this cancer. A growing body of literature documents that ectopic expression of these genes is not a mere indication of deregulated cellular processes, but an important mechanism of tumorigenesis and cancer progression. A summary of different classes of ectopically expressed genes in this cancer is presented in figure 1

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References:

  1. Litvinov IV, Cordeiro B, Huang Y, Zargham H, Pehr K, Dore M, GilbertM Zhou Y, Kupper TS, Sassevile D. Ectopic expression of cancer testis antigens in Cutaneous T-Cell Lymphoma (CTCL) patients. Clin Cancer Res. 2014. 20(14):3799-808.
  2. Litvinov IV, Netchiporouk E, Cordeiro B, Zargham H, Pehr K, Gilbert M, Zhou Y, Moreau L, Woetmann A, Ødum N, Kupper TS, Sasseville D. Ectopic expression of embryonic stem cell and other developmental genes in Cutaneous T-Cell Lymphoma. Oncoimmunology. 2014; 3: e9700251-9700258.

 

Figure 1. Aberrant expression of embryonic stem cells genes, cancer testis genes, B cell-specific genes and thymocyte development genes may play a role in tumorigenesis/cancer progression in Cutaneous T-Cell Lymphoma . Specifically, while embryonic stem cell genes (e.g. members of the PRC2 complex) may be reprogramming cancer stem cell phenotype, cancer testis genes may be contributing to aneuploidy  and genomic instability by producing aberrant chromosomal translocations.

reprinted by permission of Taylor & Francis LLC (http://www.tandfonline.com).

Ectopic expression of cancer testis and embryonic stem cell genes in Cutaneous T-Cell lymphoma. Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

Journal Reference

Litvinov IV1, Cordeiro B2, Huang Y3, Zargham H2, Pehr K2, Doré MA4, Gilbert M4, Zhou Y3, Kupper TS5, Sasseville D1. Clin Cancer Res. 2014;20(14):3799-808. 21.

Show Affiliations

1 Division of Dermatology, McGill University Health Centre, Montréal; [email protected] [email protected]

2Division of Dermatology, McGill University Health Centre, Montréal;

3Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada; and.

4Division of Dermatology, Université Laval, Québec; and

5Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital, Harvard University, Boston, Massachusetts.

Abstract

PURPOSE:

The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains only partially understood. A number of recent studies attempted to identify novel diagnostic markers and future therapeutic targets. One group of antigens, cancer-testis (CT) antigens, normally present solely in testicular germ cells, can be ectopically expressed in a variety of cancers. Currently, only a few studies attempted to investigate the expression of CT antigens in Cutaneous T-Cell Lymphoma .

EXPERIMENTAL DESIGN:

In the present work, we test the expression of CT genes in a cohort of patients with Cutaneous T-Cell Lymphoma , normal skin samples, skin from benign inflammatory dermatoses, and in patient-derived Cutaneous T-Cell Lymphoma  cells. We correlate such expression with the p53 status and explore molecular mechanisms behind their  ectopic expression in these cells.

RESULTS:

Our findings demonstrate that SYCP1, SYCP3, REC8, SPO11, and GTSF1 genes are heterogeneously expressed in patients with Cutaneous T-Cell Lymphoma and patient-derived cell lines, whereas cTAGE1 (cutaneous T-cell lymphoma-associated antigen 1) was found to be robustly expressed in both. Mutated p53 status did not appear to be a requirement for the ectopic expression of CT antigens. While T-cell stimulation resulted in a significant upregulation of STAT3 and JUNB expression, it did not significantly alter the expression of CT antigens. Treatment of Cutaneous T-Cell Lymphoma cells in vitro with vorinostat or romidepsin histone deacetylase inhibitors resulted in a significant dose-dependent upregulation of mRNA but not protein. Further expression analysis demonstrated that SYCP1, cTAGE1, and GTSF1 were expressed in Cutaneous T-Cell Lymphoma , but not in normal skin or benign inflammatory dermatoses.

CONCLUSIONS:

A number of CT genes are ectopically expressed in patients with Cutaneous T-Cell Lymphoma and can be used as biomarkers  or novel targets for immunotherapy.

©2014 American Association for Cancer Research.

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