Cancer/testis genes in multiple myeloma: expression patterns and prognosis value determined by microarray analysis.

Institute of Research in Biotherapy, Centre Hospitalier Universitaire Montpellier, Montpellier, France.
The Journal of Immunology (Impact Factor: 5.36). 04/2007; 178(5):3307-15. DOI: 10.4049/jimmunol.178.5.3307
Source: PubMed

ABSTRACT Cancer-testis (CT) Ags are expressed in testis and malignant tumors but rarely in nongametogenic tissues. Due to this pattern, they represent attractive targets for cancer vaccination approaches. The aims of the present study are: 1) to assess the expression of CT genes on a pangenomic base in multiple myeloma (MM); 2) to assess the prognosis value of CT gene expression; and 3) to provide selection strategies for CT Ags in clinical vaccination trials. We report the expression pattern of CT genes in purified MM cells (MMC) of 64 patients with newly diagnosed MM and12 patients with monoclonal gammopathy of unknown significance, in normal plasma cell and B cell samples, and in 20 MMC lines. Of the 46 CT genes interrogated by the Affymetrix HG-U133 set arrays, 35 are expressed in the MMC of at least one patient. Of these, 25 are located on chromosome X. The expression of six CT genes is associated with a shorter event-free survival. The MMC of 98% of the patients express at least one CT gene, 86% at least two, and 70% at least three CT genes. By using a set of 10 CT genes including KM-HN-1, MAGE-C1, MAGE-A3/6/12, MAGE-A5, MORC, DDX43, SPACA3, SSX-4, GAGE-1-8, and MAGE-C2, a combination of at least three CT genes-desirable for circumventing tumor escape mechanisms-is obtained in the MMC of 67% of the patients. Provided that the immunogenicity of the products of these 10 CT genes is confirmed, gene expression profiling could be useful in identifying which CT Ags could be used to vaccinate a given patient.

  • [Show abstract] [Hide abstract]
    ABSTRACT: DEAD box polypeptide 43 (DDX43), a cancer/testis antigen (CTA), has been found to be overexpressed in various solid tumors and some hematologic malignancies. In the present work hypomethylation of the DDX43 gene was detected in 15% (32/214) of primary acute myeloid leukemia (AML) using real-time quantitative methylation-specific PCR (RQ-MSP). The level of DDX43 expression was correlated with DDX43 hypomethylation (R = 0.277, P = 0.014). Moreover, bisulfite sequencing confirmed the significant correlation between the methylation density and the level of DDX43 hypomethylation. Additionally, restoration of DDX43 expression in the K562 cell line by 5-aza-2′-deoxycytidine treatment confirmed a direct contribution of methylation in regulating the DDX43 gene. DDX43 hypomethylation was observed more frequently in favorable group (21.4%) and intermediate group (15.8%) than in poor group (0%) (P = 0.009). AML patients with DDX43 hypomethylation had a better overall survival (median not obtained) than those with DDX43 methylation (median 8 months, 95% confidence interval 5.6-10.4 months) (P = 0.014). In summary, the DDX43 gene is activated by promoter hypomethylation and DDX43 hypomethylation may be a favorable prognostic factor in AML.
    Leukemia research 05/2014; · 2.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim: The present study aimed at correlating the expression of cancer/testis antigens (CTAs) with the expression of genes related to tumor-infiltrating T cells. Materials & methods: MAGE-C1/CT-7, MAGEA3/6, NY-ESO-1, LAGE-1 and GAGE expression were evaluated in 46 bone marrow multiple myeloma (MM) aspirates by RT-PCR. Expression of FOXP3/CTLA4 and RORyt, as markers for Tregs and Th17 cells, respectively, was investigated by quantitative PCR. Results: MAGEC1/CT7 was expressed in 66% of MM samples. We did not find correlation between the presence of single CTA and expression of CTLA4 or RORyt neither expression of CD4(+) T-cell markers and the number of CTA simultaneously expressed in the tumor. However, we did observe a correlation between the percentage of plasma cells and the number of CTAs expressed in the patients' bone marrow. Conclusion: Although CTAs and immunomodulatory CD4(+) T cells represent potential targets for immunotherapy in MM, we did not find association among expression of such genes in MM.
    Immunotherapy 05/2014; 6(5):569-575. · 2.44 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Myeloma is characterized by highly variable clinical outcome. Despite the effectiveness of high-dose therapy, 15% patients relapse within 1 year. We show that these cases also have a significantly shorter post-relapse survival compared to the others (median 14.9 months v.s. 40 months, p = 8.03x10(-14)). There are no effective approaches to define this potentially distinct biological group, such that treatment could be altered. In this work a series of uniformly treated myeloma patients were used to develop a gene expression profiling (GEP)-based signature to identify this high risk clinical behaviour. Gene enrichment analyses applied to the top differentially expressed genes showed a significant enrichment of epigenetic regulators as well as "stem cell" myeloma genes. A derived 17-gene signature effectively identifies patients at high risk of early relapse as well as impaired overall survival. Integrative genomic analyses showed that epigenetic mechanisms may play an important role on transcription of these genes.
    Leukemia and Lymphoma 06/2014; · 2.61 Impact Factor

Full-text (2 Sources)

Available from
May 31, 2014