Gene Summary

Gene:MAGEA1; melanoma antigen family A1
Aliases: CT1.1, MAGE1
Summary:This gene is a member of the MAGEA gene family. The members of this family encode proteins with 50 to 80% sequence identity to each other. The promoters and first exons of the MAGEA genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. The MAGEA genes are clustered at chromosomal location Xq28. They have been implicated in some hereditary disorders, such as dyskeratosis congenita. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:melanoma-associated antigen 1
Source:NCBIAccessed: 17 March, 2015


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 March 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 17 March, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: MAGEA1 (cancer-related)

Grah JJ, Katalinic D, Juretic A, et al.
Clinical significance of immunohistochemical expression of cancer/testis tumor-associated antigens (MAGE-A1, MAGE-A3/4, NY-ESO-1) in patients with non-small cell lung cancer.
Tumori. 2014 Jan-Feb; 100(1):60-8 [PubMed] Related Publications
AIMS AND BACKGROUND: This paper deals with the clinical significance of the immunohistochemical expression of MAGE-A1, MAGE-A3/4 and NY-ESO-1 antigens in patients with non-small cell lung cancer (NSCLC).
METHODS AND STUDY DESIGN: The study included 80 patients with NSCLC (40 with adenocarcinoma, 40 with squamous cell carcinoma) who had undergone surgery. MAGE-A1 and MAGE-A3/4 antigen expression was determined by an immunohistochemical method using the monoclonal antibody 57B, and NY-ESO-1 antigen expression was determined with the addition of the B9.8.1.1 antibody. The expression of these antigens was compared with the clinicopathological features of the tumors and the survival of the patients.
RESULTS: MAGE-A1, MAGE-A3/4 and NY-ESO-1 were expressed in 17.3%, 44.4% and 18.5% of NSCLC patients, respectively. A statistically higher immunohistological expression rate of MAGE-A3/4 was found in squamous cell carcinoma (P <0.001) and a significantly higher amount of tumor necrosis was observed in tumors with MAGE-3 expression (P = 0.001), but no correlation with positive lymph nodes was found. There was a statistically significant correlation between MAGE-A1 expression in adenocarcinoma and the presence of tumor necrosis (P = 0.05). Furthermore, there was a significant correlation between NY-ESO-1 expression and positive lymph nodes in adenocarcinoma, but not in squamous cell carcinoma. No statistically significant difference in patient survival was found with regard to tumor type and the observed histopathological characteristics except tumor size. Statistically significantly better survival was found in the group of patients with adenocarcinomas who had positive expression of MAGE-A3/4 (P = 0.012).
CONCLUSIONS: This study demonstrated that the expression of MAGE-A3/4 antigen might be a valuable prognostic factor regarding survival in patients with NSCLC.

Hemminger JA, Toland AE, Scharschmidt TJ, et al.
Expression of cancer-testis antigens MAGEA1, MAGEA3, ACRBP, PRAME, SSX2, and CTAG2 in myxoid and round cell liposarcoma.
Mod Pathol. 2014; 27(9):1238-45 [PubMed] Free Access to Full Article Related Publications
Myxoid and round-cell liposarcoma is a frequently encountered liposarcoma subtype. The mainstay of treatment remains surgical excision with or without chemoradiation. However, treatment options are limited in the setting of metastatic disease. Cancer-testis antigens are immunogenic antigens with the expression largely restricted to testicular germ cells and various malignancies, making them attractive targets for cancer immunotherapy. Gene expression studies have reported the expression of various cancer-testis antigens in liposarcoma, with mRNA expression of CTAG1B, CTAG2, MAGEA9, and PRAME described specifically in myxoid and round-cell liposarcoma. Herein, we further explore the expression of the cancer-testis antigens MAGEA1, ACRBP, PRAME, and SSX2 in myxoid and round-cell liposarcoma by immunohistochemistry in addition to determining mRNA levels of CTAG2 (LAGE-1), PRAME, and MAGEA3 by quantitative real-time PCR. Samples in formalin-fixed paraffin-embedded blocks (n=37) and frozen tissue (n=8) were obtained for immunohistochemistry and quantitative real-time PCR, respectively. Full sections were stained with antibodies to MAGEA1, ACRBP, PRAME, and SSX2 and staining was assessed for intensity (1-2+) and percent tumor positivity. The gene expression levels of CTAG2, PRAME, and MAGEA3 were measured by quantitative real-time PCR. In total, 37/37 (100%) of the samples showed predominantly strong, homogenous immunoreactivity for PRAME. There was a variable, focal expression of MAGEA1 (11%) and SSX2 (16%) and no expression of ACRBP. Quantitative real-time PCR demonstrated PRAME and CTAG2 transcripts in all eight samples: six tumors with high mRNA levels; two tumors with low mRNA levels. The gene expression of MAGEA3 was not detected in the majority of cases. In conclusion, myxoid and round-cell liposarcomas consistently express PRAME by immunohistochemistry as well as CTAG2 and PRAME by qualitative real-time PCR. This supports the use of cancer-testis antigen-targeted immunotherapy in the treatment of this malignancy.

Hudolin T, Kastelan Z, Ilic I, et al.
Immunohistochemical analysis of the expression of MAGE-A and NY-ESO-1 cancer/testis antigens in diffuse large B-cell testicular lymphoma.
J Transl Med. 2013; 11:123 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Primary testicular lymphoma (PTL) is a rare and lethal disease. The most common histological subtype is diffuse large B-cell lymphoma (DLBCL). Standard treatments are frequently ineffective. Thus, the development of novel forms of therapy is urgently required. Specific immunotherapy generating immune responses directed against antigen predominantly expressed by cancer cells such as cancer-testis antigens (CTA) may provide a valid alternative treatment for patients bearing PTL, alone or in combination with current therapies.
METHODS: Three monoclonal antibodies (mAbs), 77B recognizing MAGE-A1, 57B recognizing an epitope shared by multiple MAGE-A CTA (multi-MAGE-A specific) and D8.38 recognizing NY-ESO-1/LAGE-1 were used for immunohistochemical staining of 27 PTL, including 24 DLBCL.
RESULTS: Expression of MAGE-A1 was infrequently detectable in DLBCL specimens (12.50%), whereas multi-MAGE-A and NY-ESO-1/LAGE-1 specific reagents stained the cytoplasms of tumor cells in DLBCL specimens with higher frequencies (54.17% and 37.50%, respectively) with different expression levels.
CONCLUSIONS: These results suggest that MAGE-A and NY-ESO-1/LAGE-1, possibly in combination with other CTA, might be used as targets for specific immunotherapy in DLBCL.

Lee HS, Kim SW, Hong JC, et al.
Expression of MAGE A1-6 and the clinical characteristics of papillary thyroid carcinoma.
Anticancer Res. 2013; 33(4):1731-5 [PubMed] Related Publications
BACKGROUND: The expression of melanoma-associated antigen (MAGE) gene has been studied in many types of cancer. In the present study we evaluated the correlation between MAGE expression and the clinical features and oncologic outcomes of patients with papillary thyroid cancer (PTC).
MATERIALS AND METHODS: We performed a retrospective review of 85 patients who underwent surgery for PTC and analysis of their tumor tissue by nested reverse transcription-polymerase chain reaction (RT-PCR) with the MAGE common primer to detect the MAGE A1-6 gene. The associations between MAGE expression and clinical characteristics were analyzed.
RESULTS: Expression of MAGE A1-6 in PTC was identified in 31 patients (36.5%). Only papillary thyroid microcarcinoma (PTMC) was significantly related to MAGE expression in our univariate analysis (p=0.002) and multivariate analysis (p=0.006). MAGE had no significant impact on survival.
CONCLUSION: Expression of MAGE A1-6 in PTC is significantly correlated with the presence of PTMC. Our study suggests that MAGE expression may be related to early-stage PTC.

Cannuyer J, Loriot A, Parvizi GK, De Smet C
Epigenetic hierarchy within the MAGEA1 cancer-germline gene: promoter DNA methylation dictates local histone modifications.
PLoS One. 2013; 8(3):e58743 [PubMed] Free Access to Full Article Related Publications
Gene MAGEA1 belongs to a group of human germline-specific genes that rely on DNA methylation for repression in somatic tissues. Many of these genes, termed cancer-germline (CG) genes, become demethylated and activated in a wide variety of tumors, where they encode tumor-specific antigens. The process leading to DNA demethylation of CG genes in tumors remains unclear. Previous data suggested that histone acetylation might be involved. Here, we investigated the relative contribution of DNA methylation and histone acetylation in the epigenetic regulation of gene MAGEA1. We show that MAGEA1 DNA hypomethylation in expressing melanoma cells is indeed correlated with local increases in histone H3 acetylation (H3ac). However, when MAGEA1-negative cells were exposed to a histone deacetylase inhibitor (TSA), we observed only short-term activation of the gene and detected no demethylation of its promoter. As a more sensitive assay, we used a cell clone harboring a methylated MAGEA1/hph construct, which confers resistance to hygromycin upon stable re-activation. TSA induced only transient de-repression of the transgene, and did not lead to the emergence of hygromycin-resistant cells. In striking contrast, transient depletion of DNA-methyltransferase-1 in the reporter cell clone gave rise to a hygromycin-resistant population, in which the re-activated MAGEA1/hph transgene displayed not only marked DNA hypomethylation, but also significant reversal of histone marks, including gains in H3ac and H3K4me2, and losses of H3K9me2. Collectively, our results indicate that DNA methylation has a dominant role in the epigenetic hierarchy governing MAGEA1 expression.

Hartmann S, Kriegebaum U, Küchler N, et al.
Efficacy of cetuximab and panitumumab in oral squamous cell carcinoma cell lines: prognostic value of MAGE-A subgroups for treatment success.
J Craniomaxillofac Surg. 2013; 41(7):623-9 [PubMed] Related Publications
BACKGROUND: Over-expression of epidermal growth factor receptor (EGFR) has been observed in a variety of epithelial tumours. The selective inhibition of the associated signalling pathway using monoclonal antibodies appears to be a promising therapeutic target. Individual differences in response rates, particularly against highly selective chemotherapeutic agents, underline the need for further research of the molecular basis of this process. Previously described resistance mechanisms are not able to explain all refractory responses. Several subgroups of the melanoma-associated antigens (MAGE) tumour antigens were described in connection with regulatory functions relating to the cell cycle and chemosensitivity.
METHODS: In the present study, five cell lines of human squamous cell carcinomas were treated with cetuximab and panitumumab (0.01-100 μg/ml) over a period of 24 or 48 h. The efficacy of the agents used was measured dynamically using real-time cell analysis (RTCA). Subsequently, the expression levels of MAGE-A1, -A5, -A8, -A9, -A11 and -A12 were determined by RT-qPCR. A correlation between chemosensitivity and MAGE-A expression was investigated.
RESULTS: The tumour cell lines exhibited a very low overall response to the chemotherapy drugs. Only one cell line showed a cytostatic effect after treatment with cetuximab and panitumumab. This effect, however, was significant only for panitumumab. The expression of MAGE-A12 was significantly associated with greater efficacy of panitumumab. The expression of MAGE-A5 and -A8 was associated with poorer response rates after panitumumab treatment. Due to an insignificant effect of cetuximab on the number of viable cells, no correlation with the MAGE-A levels was observed.
CONCLUSION: For the first time, these results show a correlation between the efficacies of EGFR inhibitors and various MAGE-A subgroups in the treatment of HNSCC. Determining the MAGE-A status could help to improve the success of anti-tumour drug therapy. In addition, evaluating MAGE-A levels might be an important tool in the development of patient-specific treatment protocols.

Bhan S, Chuang A, Negi SS, et al.
MAGEA4 induces growth in normal oral keratinocytes by inhibiting growth arrest and apoptosis.
Oncol Rep. 2012; 28(4):1498-502 [PubMed] Related Publications
Cancer testis antigens (CTAs) are proteins that are normally expressed only in male germ cells and are aberrantly upregulated in a variety of cancers such as melanomas and lung cancer. MAGEA proteins belong to Class I CTAs and are being utilized as targets for cancer immunotherapy. Despite the discovery of the first CTA (MAGEA1) 20 years ago, the functions of these proteins remain poorly understood and evidence suggests both oncogenic as well as tumor suppressive roles for these proteins. Herein, we investigated the role of MAGEA4 in promoting cell growth. When overexpressed, MAGEA4 promotes growth of spontaneously transformed normal oral keratinocytes (NOK-SI). To understand the mechanism of growth stimulation by MAGEA4, we explored the effect of overexpressing MAGEA4 on cell cycle and apoptosis. MAGEA4 inhibits growth arrest of cells in the G1 phase of the cell cycle. We also found that overexpression of MAGEA4 inhibits G418-induced apoptosis of NOK-SI cells. Interestingly, this inhibition was accompanied by repression of two p53 downstream genes, BAX and CDKN1A. Our results indicate that MAGEA4 promotes growth by preventing cell cycle arrest and by inhibiting apoptosis mediated by the p53 transcriptional targets.

Park JH, Do NY, Han SI, Lim SC
Usefulness of the melanoma antigen gene (MAGE) in making the differential diagnosis between pleomorphic adenoma and adenoid cystic carcinoma.
J Otolaryngol Head Neck Surg. 2012; 41(1):20-9 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to examine the clinical usefulness of the melanoma antigen gene (MAGE) in making the differential diagnosis between pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC). In addition, using real-time reverse transcriptase polymerase chain reaction (RT-PCR), we examined which melanoma antigen gene was actually expressed in each tumour.
MATERIALS AND METHOD: Immunohistochemical staining was performed on samples of paraffin-embedded tissue specimens. Fifty-eight patients were diagnosed as PA (n  =  31), ACC (n  =  17), and nontumoral salivary tissue (n  =  10) using MAGEA and MAGEA4. Using primers that could express MAGEA1, -A2, -A3, -A4, -A6, -A10, and -A12 subtypes, real-time RT-PCR was performed in three cases of PA and four cases of ACC that occurred in fresh tissues.
RESULT: We found no immunohistochemical expression of MAGEA or MAGEA4 in the nontumoral tissue. There was a mild degree of expression with no statistical significance in cases of PA. In ACC, however, in 17 cases (100%) and 16 cases (95%), there was a positive reaction to MAGEA and MAGEA4, respectively. In the RT-PCR analysis, PA showed no MAGE gene expression. However, both MAGEA3 and MAGEA4 were expressed in ACC.
CONCLUSION: These results suggest that MAGE could be used as a biologic marker in the differential diagnosis between PA and ACC. Our results also indicate that the expression of MAGE, as confirmed in the RT-PCR analysis, could be used as an alternative method for the early diagnosis of salivary gland tumours.

Pereira CM, Gomes CC, De Fátima Correia Silva J, et al.
Evaluation of MAGE A1 in oral squamous cell carcinoma.
Oncol Rep. 2012; 27(6):1843-8 [PubMed] Related Publications
MAGE A1 is a cancer testis antigen (CTA) described in a variety of human cancers. CTAs exhibit a highly restricted tissue expression and by virtue of their immunogenic potential, these genes are promising target molecules for cancer vaccines. DNA hypomethylation is associated with gene regulation in several types of tumours. The aim of this project was to identify the presence of MAGE A1 in oral squamous cell carcinoma (OSCC) samples and to investigate the hypomethylation profile of CpG islands situated in the promoter region of this gene. The expression of MAGE A1 in OSCC and healthy oral mucosal samples was determined by real-time quantitative and conventional endpoint PCR and also by immunohistochemistry staining. In addition, to investigate the hypomethylation profile of promoter MAGE A1 CpG islands, we performed bisulphite sequencing. Real-time quantitative and endpoint PCR assays demonstrated a lower level of MAGE A1 transcription. Endpoint PCR showed expression of MAGE A1 in 10% (2/20) of OSCCs. Sodium bisulphite sequencing analysis of MAGE A1 CpG islands did not reveal a difference between OSCC and normal oral mucosal samples. We further assessed MAGE A1 protein immunoexpression and found 80% (16/20) of immunopositivity in OSCCs. We did not observe a correlation between the presence of MAGE A1 protein and lower levels of transcripts. Identification of MAGE A1 protein in OSCCs and absence of immunoexpression in normal oral mucosa support the idea that this protein can be used as a biomarker for detection of OSCC; however, it is not associated with hypomethylation or high expression of the MAGE A1 gene.

Cucuruz B, Dango S, Jurinovic V, et al.
MAGE qPCR improves the sensitivity and accuracy of EBUS-TBNA for the detection of lymphatic cancer spread.
J Thorac Oncol. 2012; 7(4):690-7 [PubMed] Related Publications
INTRODUCTION: Microscopic examination of histologic slides or cytologic specimens of mediastinal lymph node samples obtained by diagnostic mediastinoscopy or endobronchial ultrasound-guided fine-needle aspiration (EBUS-TBNA) is routinely used for the staging of lung cancer patients. Therefore, we explored whether the detection of tumor-associated mRNA in lymph node samples from patients with suspected lung cancer adds diagnostic accuracy to conventional histopathological staging.
METHODS: We examined 202 lymph nodes obtained by EBUS-TBNA or mediastinoscopy from 89 patients with lung cancer. Lymph node samples from patients with nonmalignant disease were available as controls (60 samples from 31 patients). Real-time quantitative mRNA analysis was performed for melanoma antigen-A genes (MAGE-A 1-6, MAGE-A 12) using a LightCycler 480 instrument.
RESULTS: MAGE transcript levels in control and cancer patients differed widely, and the 95% confidence interval served to define the threshold between negative and positive samples. MAGE 1 to 6 transcripts were detected in 35 of 122 (28.7%) lymph nodes obtained by EBUS-TBNA and 16 of 80 (20.0%) lymph nodes obtained by mediastinoscopy. MAGE 12 transcripts were detected in 10 of 122 (8.2%) lymph nodes obtained by EBUS-TBNA and 9 of 80 (11.3%) lymph nodes obtained by mediastinoscopy. Although the accuracy of histopathological diagnosis after EBUS-TBNA and mediastinoscopy was 69.6% and 84.1%, respectively, it increased to 81.2% and 86.4%, respectively, when combined with MAGE-quantitative polymerase chain reaction.
CONCLUSIONS: The combination of EBUS-TBNA and MAGE-quantitative polymerase chain reaction increases the accuracy of tumor cell detection to the level seen with mediastinoscopy.

Shin KC, Choi EY, Chung JH, et al.
Clinical application of MAGE A1-6 RT-nested PCR for diagnosis of lung cancer invisible by bronchoscopy.
Anticancer Res. 2012; 32(1):163-7 [PubMed] Related Publications
BACKGROUND: The main goal of this study was to evaluate the diagnostic efficacy of melanoma-associated antigen (MAGE) A1-6 reverse transcriptase-nested polymerase chain reaction (RT-nested PCR) of bronchial washing fluid for the detection of lung cancer invisible by bronchoscopy.
PATIENTS AND METHODS: To determine the expression of MAGE A1-6 gene in 75 lung carcinomas diagnosed by conventional fluoroscopy-guided lung biopsy and 58 cancer-free controls, RT-nested PCR was performed of bronchial washing fluid. MAGE A1-6 RT-nested PCR data was analyzed according to tumor histology, stage, size, and compared with cytological data.
RESULTS: MAGE A1-6 RT-nested PCR displayed higher sensitivity (64.0%) than that of conventional cytology (14.7%). There was no significant correlation between MAGE gene expression and histological types or clinical stage. For tumor size, detection rates were 74.0% in tumor smaller than 3 cm and 58.7% in these larger than 3 cm.
CONCLUSIONS: MAGE A1-6 RT-nested PCR of bronchial washing fluid may be a useful method for diagnosis of peripheral lung cancer in clinical practice.

Shin KC, Lee KH, Lee CH, et al.
MAGE A1-A6 RT-PCR and MAGE A3 and p16 methylation analysis in induced sputum from patients with lung cancer and non-malignant lung diseases.
Oncol Rep. 2012; 27(4):911-6 [PubMed] Free Access to Full Article Related Publications
The melanoma antigen gene (MAGE) A1-A6 RT-PCR system was developed for the detection of lung cancer cells in the sputum. However, we identified MAGE expression in some patients with non-malignant lung diseases. To understand these patterns of MAGE expression, we performed MAGE A3 methylation-specific PCR (MSP) and p16 MSP. We collected 24 biopsy specimens of lung cancer tissue and performed MAGE A1-A6 RT-PCR, MAGE A3 MSP and p16 MSP. RNA and DNA were simultaneously extracted from induced sputum specimens of 133 patients with lung diseases and 30 random sputum specimens of healthy individuals and the 3 molecular analyses were performed. The patients were diagnosed as 65 cases of lung cancer and 68 of benign lung diseases. Positive rates of MAGE A1-A6 RT-PCR, MAGE A3 MSP and p16 MSP were as follows: in lung cancer tissue, 87.5, 58.3 and 70.8%; in the sputum of lung cancer patients, 50.8, 46.2 and 63.1%; benign lung diseases, 10.3, 30.9 and 39.7%; and healthy individuals, 3.3, 6.7 and 3.3%. Of the 40 MAGE-positive cases, 33 were diagnosed with lung cancer and 7 as having benign lung diseases. From the 7 cases of MAGE-positive benign lung diseases, 6 cases showed methylation abnormalities. The MAGE-positive group revealed significantly higher rates of methylation abnormalities. Of the 40 MAGE-positive cases, 39 cases were found to be lung cancer or benign lung diseases with abnormal methylation. Thus, MAGE expression in the sputum suggests the presence of lung cancer cells or pre-cancerous cells.

Goodyear OC, Pearce H, Pratt G, Moss P
Dominant responses with conservation of T-cell receptor usage in the CD8+ T-cell recognition of a cancer testis antigen peptide presented through HLA-Cw7 in patients with multiple myeloma.
Cancer Immunol Immunother. 2011; 60(12):1751-61 [PubMed] Related Publications
Cancer testis antigens exhibit physiological expression within germ cells and are frequently expressed in malignant tissue. Interestingly, immunological tolerance to cancer testis proteins does not appear to be established, and the expression of CTAg proteins within malignant cells can therefore lead to induction of cellular and humoral immunity. A considerable body of evidence now indicates that CD8-specific immunity plays an important role in the control of cancer cell growth, and a number of vaccine studies are in progress to boost CTAg-specific cellular immune responses. We have previously identified CTAg-specific immune responses in patients with multiple myeloma and reported that recognition of the MAGE-A1(289-298) peptide, which is described as being restricted by HLA-B*0702, was the most frequent response seen with our peptide panel. Here, we studied seven CD8+ T-cell clones specific for this peptide which were isolated from three patients with myeloma at several time-points. The affinity of peptide recognition was high with 50% maximal interferon-γ production observed at a peptide concentration of 10(-10) M and variation of only one order of magnitude between the affinities of the clones. Importantly, all the clones were able to recognise and kill multiple myeloma cell lines. Interestingly, one patient did not express HLA-B*0702, but three clones from this patient recognised the MAGE-A1(289-298) peptide on a lymphoblastoid cell line (LCLs) expressing HLA-Cw7, and we now show evidence that the MAGE-A1(289-298) peptide is expressed and recognised through Cw7. The T-cell receptor gene usage was determined in five clones and showed conserved features in both the α and the β chain genes indicating correlation between T-cell receptor usage and peptide specificity of cancer testis antigen-specific T-cell clones.

Karn T, Pusztai L, Ruckhäberle E, et al.
Melanoma antigen family A identified by the bimodality index defines a subset of triple negative breast cancers as candidates for immune response augmentation.
Eur J Cancer. 2012; 48(1):12-23 [PubMed] Related Publications
BACKGROUND: Molecular markers displaying bimodal expression distribution can reveal distinct disease subsets and may serve as prognostic or predictive markers or represent therapeutic targets. Oestrogen (ER) and human epidermal growth factor receptor 2 (HER2) receptors are strongly bimodally expressed genes in breast cancer.
MATERIAL AND METHODS: We applied a novel method to identify bimodally expressed genes in 394 triple negative breast cancers (TNBC). We identified 133 bimodally expressed probe sets (128 unique genes), 69 of these correlated to previously reported metagenes that define molecular subtypes within TNBC including basal-like, molecular-apocrine, claudin-low and immune cell rich subgroups but 64 probe sets showed no correlation with these features.
RESULTS: The single most prominent functional group among these uncorrelated genes was the X chromosome derived Cancer/Testis Antigens (CT-X) including melanoma antigen family A (MAGE-A) and Cancer/Testis Antigens (CTAG). High expression of CT-X genes correlated with worse survival in multivariate analysis (HR 2.02, 95% CI 1.27-3.20; P=0.003). The only other significant variable was lymph node status. The poor prognosis of patients with high MAGE-A expression was ameliorated by the concomitant high expression of immune cell metagenes (HR 1.87, 95% CI 0.96-3.64; P=0.060), whereas the same immune metagene had lesser prognostic value in TNBC with low MAGE-A expression.
CONCLUSIONS: MAGE-A antigen defines a very aggressive subgroup of TNBC; particularly in the absence of immune infiltration in the tumour microenvironment. These observations suggest a therapeutic hypothesis; TNBC with MAGE-A expression may benefit the most from further augmentation of the immune response. Novel immune stimulatory drugs such as (anti-cytotoxic T-lymphocyte antigen-4 CTLA-4) directed therapies provide a realistic opportunity to directly test this hypothesis in the clinic.

Rao M, Chinnasamy N, Hong JA, et al.
Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer.
Cancer Res. 2011; 71(12):4192-204 [PubMed] Free Access to Full Article Related Publications
Cancer-testis antigens (CTA), such as NY-ESO-1, MAGE-A1, and MAGE-A3, are immunogenic proteins encoded by genes, which are normally expressed only in male germ cells but are activated by ill-defined epigenetic mechanisms in human tumors, including lung cancers. Previously, we reported induction of these CTAs in cancer cells, but not normal cells, by DNA-demethylating agents and histone deacetylase inhibitors using clinically achievable exposure conditions. In the present study, we evaluated chromatin alterations associated with repression/activation of cancer-testis genes in lung cancer cells to further develop gene-induction regimens for cancer immunotherapy. Repression of NY-ESO-1, MAGE-A1, and MAGE-A3 coincided with DNA hypermethylation, recruitment, and binding of polycomb-group proteins, and histone heterochromatin modifications within the promoters of these genes. Derepression coincided with DNA demethylation, dissociation of polycomb proteins, and presence of euchromatin marks within the respective promoters. Short hairpin RNAs were used to inhibit several histone methyltransferases (KMT) and histone demethylases (KDM) that mediate histone methylation and repress gene expression. Knockdown of KMT6, KDM1, or KDM5B markedly enhanced deoxyazacytidine (DAC)-mediated activation of these cancer-testis genes in lung cancer cells. DZNep, a pharmacologic inhibitor of KMT6 expression, recapitulated the effects of KMT6 knockdown. Following DAC-DZNep exposure, lung cancer cells were specifically recognized and lysed by allogeneic lymphocytes expressing recombinant T-cell receptors recognizing NY-ESO-1 and MAGE-A3. Combining DNA-demethylating agents with compounds, such as DZNep, that modulate histone lysine methylation may provide a novel epigenetic strategy to augment cancer-testis gene expression as an adjunct to adoptive cancer immunotherapy.

Yanagawa N, Tamura G, Oizumi H, et al.
MAGE expressions mediated by demethylation of MAGE promoters induce progression of non-small cell lung cancer.
Anticancer Res. 2011; 31(1):171-5 [PubMed] Related Publications
BACKGROUND: The MAGE gene encodes cancer/testis antigens that are recognized on melanoma cells by autologous cytolytic T lymphocytes. These genes are expressed in various tumor cells, but not in healthy tissues except for the testis and placenta. MAGE expression is known to be activated by promoter demethylation.
MATERIALS AND METHODS: The expression of MAGE-A1 and -A3 and promoter methylation of MAGE-A1 and -A3 was investigated in 67 non-small cell lung cancer (NSCLC) specimens and their correlation with clinicopathological parameters was elucidated.
RESULTS: Expression of MAGE-A1 and -A3 was detected in 29.9% and 38.8% of the cases. Demethylation of MAGE-A1 and -A3 was detected in 41.8% and 46.3% of the cases. In 18 (of 20) cases, MAGE-A1 expression showed demethylation of MAGE-A1 and in 24 (of 26) cases MAGE-A3 expression showed demethylation of MAGE-A3. The patients with MAGE expression had a worse prognosis than those with no MAGE expression.
CONCLUSION: MAGE expression mediated by demethylation of MAGE promoters is associated with aggressive progression of NSCLC.

Corbière V, Chapiro J, Stroobant V, et al.
Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases.
Cancer Res. 2011; 71(4):1253-62 [PubMed] Related Publications
A core challenge in cancer immunotherapy is to understand the basis for efficacious vaccine responses in human patients. In previous work we identified a melanoma patient who displayed a low-level antivaccine cytolytic T-cell (CTL) response in blood with tumor regression after vaccination with melanoma antigens (MAGE). Using a genetic approach including T-cell receptor β (TCRβ) cDNA libraries, we found very few antivaccine CTLs in regressing metastases. However, a far greater number of TCRβ sequences were found with several of these corresponding to CTL clones specific for nonvaccine tumor antigens, suggesting that antigen spreading was occurring in regressing metastases. In this study, we found another TCR belonging to tumor-specific CTL enriched in regressing metastases and detectable in blood only after vaccination. We used the TCRβ sequence to detect and clone the desired T cells from tumor-infiltrating lymphocytes isolated from the patient. This CD8 clone specifically lysed autologous melanoma cells and displayed HLA-A2 restriction. Its target antigen was identified as the mitochondrial enzyme caseinolytic protease. The target antigen gene was mutated in the tumor, resulting in production of a neoantigen. Melanoma cell lysis by the CTL was increased by IFN-γ treatment due to preferential processing of the antigenic peptide by the immunoproteasome. These results argue that tumor rejection effectors in the patient were indeed CTL responding to nonvaccine tumor-specific antigens, further supporting our hypothesis. Among such antigens, the mutated antigen we found is the only antigen against which no T cells could be detected before vaccination. We propose that antigen spreading of an antitumor T-cell response to truly tumor-specific antigens contributes decisively to tumor regression.

Weeraratne SD, Amani V, Neiss A, et al.
miR-34a confers chemosensitivity through modulation of MAGE-A and p53 in medulloblastoma.
Neuro Oncol. 2011; 13(2):165-75 [PubMed] Free Access to Full Article Related Publications
Recent studies have established miR-34a as a key effector of the p53 signaling pathway and have implicated its role in multiple cancer types. Here, we establish that miR-34a induces apoptosis, G2 arrest, and senescence in medulloblastoma and renders these cells more sensitive to chemotherapeutic agents. These effects are mediated in part by the direct post-transcriptional repression of the oncogenic MAGE-A gene family. We demonstrate that miR-34a directly targets the 3' untranslated regions of MAGE-A genes and decreases MAGE-A protein levels. This decrease in MAGE-A results in a concomitant increase in p53 and its associated transcriptional targets, p21/WAF1/CIP1 and, importantly, miR-34a. This establishes a positive feedback mechanism where miR-34a is not only induced by p53 but increases p53 mRNA and protein levels through the modulation of MAGE-A genes. Additionally, the forced expression of miR-34a or the knockdown of MAGE-A genes by small interfering RNA similarly sensitizes medulloblastoma cells to several classes of chemotherapeutic agents, including mitomycin C and cisplatin. Finally, the analysis of mRNA and micro-RNA transcriptional profiles of a series of primary medulloblastomas identifies a subset of tumors with low miR-34a expression and correspondingly high MAGE-A expression, suggesting the coordinate regulation of these genes. Our work establishes a role for miR-34a in modulating responsiveness to chemotherapy in medulloblastoma and presents a novel positive feedback mechanism involving miR-34a and p53, via direct targeting of MAGE-A.

Ogata K, Aihara R, Mochiki E, et al.
Clinical significance of melanoma antigen-encoding gene-1 (MAGE-1) expression and its correlation with poor prognosis in differentiated advanced gastric cancer.
Ann Surg Oncol. 2011; 18(4):1195-203 [PubMed] Related Publications
BACKGROUND: Melanoma antigen-encoding gene-1 (MAGE-1), a cancer/testis antigen, has been reported to be expressed in various types of cancer. We investigated the clinicopathological features and prognostic significance of MAGE-1 expression in advanced gastric cancer (AGC).
METHODS: Immunohistochemical staining for MAGE-1 was performed on surgical specimens obtained from 135 patients with AGC.
RESULTS: Positive expression of MAGE-1 detected in cytoplasm was observed in 44 of 135 cases (32.6%) in primary tumors and 26 of 96 (27.1%) in lymph node metastases. In noncancerous gastric tissues, apparent MAGE-1 expression was not detected. MAGE-1 in primary tumor was correlated with advanced age (P < 0.001), macroscopic infiltrated type (P = 0.035), and presence of vascular invasion (P = 0.027). The 5-year cancer-specific survival rates of AGC patients with positive MAGE-1 expression were significantly lower than those of patients with negative MAGE-1 (positive: 31.6%, negative: 57.6%, P = 0.038). On multivariate analysis, MAGE-1 expression was not an independent prognostic predictor of AGC (P = 0.064). In differentiated AGC patients, MAGE-1 expression was correlated with advanced age (P = 0.003), macroscopic infiltrated type (P = 0.009), and presence of lymph node metastasis (P = 0.033). The cancer-specific survival rates of differentiated AGC patients with positive MAGE-1 were significantly lower than those of patients with negative MAGE-1 (P = 0.003). Positive MAGE-1 expression was an independent prognostic factor of differentiated AGC patients on multivariate analysis (P = 0.031).
CONCLUSIONS: These findings suggest that MAGE-1 protein expression can serve as a predictive marker of poor prognosis in differentiated AGC patients.

Caballero OL, Zhao Q, Rimoldi D, et al.
Frequent MAGE mutations in human melanoma.
PLoS One. 2010; 5(9) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer/testis (CT) genes are expressed only in the germ line and certain tumors and are most frequently located on the X-chromosome (the CT-X genes). Amongst the best studied CT-X genes are those encoding several MAGE protein families. The function of MAGE proteins is not well understood, but several have been shown to potentially influence the tumorigenic phenotype.
METHODOLOGY/PRINCIPAL FINDINGS: We undertook a mutational analysis of coding regions of four CT-X MAGE genes, MAGEA1, MAGEA4, MAGEC1, MAGEC2 and the ubiquitously expressed MAGEE1 in human melanoma samples. We first examined cell lines established from tumors and matching blood samples from 27 melanoma patients. We found that melanoma cell lines from 37% of patients contained at least one mutated MAGE gene. The frequency of mutations in the coding regions of individual MAGE genes varied from 3.7% for MAGEA1 and MAGEA4 to 14.8% for MAGEC2. We also examined 111 fresh melanoma samples collected from 86 patients. In this case, samples from 32% of the patients exhibited mutations in one or more MAGE genes with the frequency of mutations in individual MAGE genes ranging from 6% in MAGEA1 to 16% in MAGEC1.
SIGNIFICANCE: These results demonstrate for the first time that the MAGE gene family is frequently mutated in melanoma.

George RE, Lahti JM, Adamson PC, et al.
Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: a Children's Oncology Group study.
Pediatr Blood Cancer. 2010; 55(4):629-38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Demethylating agents may alter the expression of genes involved in chemotherapy resistance. We conducted a phase I trial to determine the toxicity and molecular effects of the demethylating agent, decitabine, followed by doxorubicin and cyclophosphamide in children with refractory solid tumors.
PROCEDURE: Stratum A included children with any solid tumor; Stratum B included neuroblastoma patients only. Patients received a 1-hr decitabine infusion for 7 days, followed by doxorubicin (45 mg/m(2)) and cyclophosphamide (1 g/m(2)) on day 7. Pharmacokinetic studies were performed after the first dose of decitabine. Biological studies included methylation and gene expression analyses of caspase-8, MAGE-1 and fetal hemoglobin (HbF), and expression profiling of pre- and post-treatment peripheral blood and bone marrow cells.
RESULTS: The maximum-tolerated dose of decitabine was 5 mg/m(2)/day for 7 days. Dose-limiting toxicities at 10 mg/m(2)/day were neutropenia and thrombocytopenia. Decitabine exhibited rapid clearance from plasma. Three of 9 patients in Stratum A and 4/12 patients in Stratum B had stable disease for > or = 4 months. Sustained MAGE-1 demethylation and increased HbF expression were observed in the majority of patients post-treatment (12/20 and 14/16, respectively). Caspase-8 promoter demethylation and gene expression were seen in 2/7 bone marrow samples. Differentially expressed genes were identified by microarray analysis.
CONCLUSION: Low-dose decitabine when combined with doxorubicin/cyclophosphamide has tolerable toxicity in children. However, doses of decitabine capable of producing clinically relevant biologic effects were not well tolerated with this combination. Alternative strategies of combining demethylating agents with non-cytotoxic, biologically targeted agents such as histone deacetylase inhibitors should be explored.

Goodyear O, Agathanggelou A, Novitzky-Basso I, et al.
Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia.
Blood. 2010; 116(11):1908-18 [PubMed] Related Publications
Epigenetic therapies, including DNA methyltransferase and histone deacetylase inhibitors, represent important new treatment modalities in hematologic malignancies, but their mechanism of action remains unknown. We reasoned that up-regulation of epigenetically silenced tumor antigens may induce an immunologically mediated antitumor response and contribute to their clinical activity. In this study, we demonstrate that azacitidine (AZA) and sodium valproate (VPA) up-regulate expression of melanoma-associated antigens (MAGE antigens) on acute myeloid leukemia (AML) and myeloma cell lines. In separate studies, we observed that prior exposure to AZA/VPA increased recognition of myeloma cell lines by a MAGE-specific CD8(+) cytotoxic T-lymphocyte (CTL) clone. We therefore measured CTL responses to MAGE antigens in 21 patients with AML or myelodysplasia treated with AZA/VPA. CTL responses to MAGE antigens were documented in only 1 patient before therapy; however, treatment with AZA/VPA induced a CTL response in 10 patients. Eight of the 11 patients with circulating MAGE CTLs achieved a major clinical response after AZA/VPA therapy. This is the first demonstration of a MAGE-specific CTL response in AML. Furthermore, it appears that epigenetic therapies have the capacity to induce a CTL response to MAGE antigens in vivo that may contribute to their clinical activity in AML.

Zhang S, Zhou X, Yu H, Yu Y
Expression of tumor-specific antigen MAGE, GAGE and BAGE in ovarian cancer tissues and cell lines.
BMC Cancer. 2010; 10:163 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To observe mRNA expression of tumor-specific antigen MAGE, BAGE and GAGE in epithelial ovarian cancer tissues and cell lines, to explore the relationship between gene expression and diagnosis, treatment and prognosis of ovarian cancer, and to evaluate the feasibility of their gene products as markers, and an immunotherapy target for ovarian cancer.
METHODS: mRNA expression of MAGE-1, MAGE-3, GAGE-1/2 and BAGE were determined by reverse transcription polymerase chain reaction (RT-PCR) in 14 cases of normal ovarian tissue, 20 cases of ovarian benign tumor specimens, 41 cases of ovarian cancer specimens, and ovarian cancer cell lines SKOV3, A2780, and COC1.
RESULTS: MAGE, GAGE and BAGE genes were not expressed in normal ovarian tissue. In benign tumors, only the MAGE gene was expressed; the expression rate of this gene in benign tumors was 15% (3/20). In ovarian cancer tissues, MAGE-1 and MAGE-3 was highly expressed, with expression rates of 53.7% (22/41) and 36.6% (15/41), while GAGE-1/2 and BAGE had relatively low expression, with rates of 26.8% (11/41) and 14.6% (6/41). In metastatic lesions of ovarian cancer, only MAGE-1 and BAGE were expressed, with expression rates of 28.6% (2/7) and 14.3% (1/7). The positive expression rates of MAGE-1 and MAGE-3 in serous cystadenocarcinoma were significantly higher than that in other types of ovarian cancer (P < 0.05). Gene expression rate was not correlated with menopause or lymph node metastasis. Positive expression of MAGE-1 and MAGE-3 was positively correlated with tumor differentiation and the clinical stage of the ovarian cancer. In addition, the positive expression rate of BAGE was significantly higher in ovarian cancer patients with ascites (P < 0.05). The mRNA expression profiles of MAGE, GAGE and BAGE in ovarian carcinoma cell lines SKOV3, A2780 and COC1 varied, but there was at least one gene expressed in each cell line.
CONCLUSION: Tumor-specific antigen MAGE, BAGE and GAGE may play a role in the occurrence and development of ovarian cancer. These genes can be used as one of the important indicators for early diagnosis, efficacy evaluation and prognostic determination of ovarian cancer.

He S, Wang L, Wu Y, et al.
CCL3 and CCL20-recruited dendritic cells modified by melanoma antigen gene-1 induce anti-tumor immunity against gastric cancer ex vivo and in vivo.
J Exp Clin Cancer Res. 2010; 29:37 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To investigate whether dendritic cell (DC) precursors, recruited by injection of chemokine ligand 3 (CCL3) and CCL20, induce anti-tumor immunity against gastric cancer induced by a DC vaccine expressing melanoma antigen gene-1 (MAGE-1) ex vivo and in vivo.
METHODS: B6 mice were injected with CCL3 and CCL20 via the tail vein. Freshly isolated F4/80-B220-CD11c+ cells cultured with cytokines were analyzed by phenotype analysis and mixed lymphocyte reaction (MLR). For adenoviral (Ad)-mediated gene transduction, cultured F4/80-B220-CD11c+ cells were incubated with Ad-MAGE-1. Vaccination of stimulated DC induced T lymphocytes. The killing effect of these T cells against gastric carcinoma cells was assayed by MTT. INF-gamma production was determined with an INF-gamma ELISA kit. In the solid tumor and metastases model, DC-based vaccines were used for immunization after challenge with MFC cells. Tumor size, survival of mice, and number of pulmonary metastatic foci were used to assess the therapeutic effect of DC vaccines.
RESULTS: F4/80-B220-CD11c+ cell numbers increased after CCL3 and CCL20 injection. Freshly isolated F4/80-B220-CD11c+ cells cultured with cytokines were phenotyically identical to typical DC and gained the capacity to stimulate allogeneic T cells. These DCs were transduced with Ad-MAGE-1, which were prepared for DC vaccines expressing tumor antigen. T lymphocytes stimulated by DCs transduced with Ad-MAGE-1 exhibited specific killing effects on gastric carcinoma cells and produced high levels of INF-gamma ex vivo. In vivo, tumor sizes of the experimental group were much smaller than both the positive control group and the negative control groups (P < 0.05). Kaplan-Meier survival curves showed that survival of the experimental group mice was significantly longer than the control groups (P < 0.05). In addition, MAGE-1-transduced DCs were also a therapeutic benefit on an established metastatic tumor, resulting in a tremendous decrease in the number of pulmonary metastatic foci.
CONCLUSIONS: CCL3 and CCL20-recruited DCs modified by adenovirus-trasnsduced, tumor-associated antigen, MAGE-1, can stimulate anti-tumor immunity specific to gastric cancer ex vivo and in vivo. This system may prove to be an efficient strategy for anti-tumor immunotherapy.

Almstedt M, Blagitko-Dorfs N, Duque-Afonso J, et al.
The DNA demethylating agent 5-aza-2'-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells.
Leuk Res. 2010; 34(7):899-905 [PubMed] Related Publications
Azanucleoside DNA-hypomethylating agents have remarkable clinical activity in myelodysplastic syndromes and acute myeloid leukemia (AML), particularly at low, non-cytotoxic doses favoring hypomethylation over cytotoxicity. Cancer/testis antigens (CTAs) encoding immunogenic proteins are not expressed in almost all normal tissues and many tumor types, but are consistently derepressed by epigenetically active agents in various cancer cell lines. Since the expression of CTA genes is usually very low or absent in myeloid leukemias, we treated various AML cell lines with 5-aza-2'-deoxycytidine (DAC) and quantified mRNA expression of the CTAs NY-ESO-1, MAGEA1, MAGEA3 and MAGEB2. Consistent time- and dose-dependent reactivation of all 4 CTA genes was observed, with maximum mRNA levels 72-144h after treatment start. As determined by RNA microarray analyses, numerous other CTA genes (all located on the X-chromosome) were also derepressed in a time-dependent fashion by DAC. NY-ESO-1 derepression was confirmed at the protein level. By Elispot and chromium release assays we showed that the de novo expressed NY-ESO-1 protein was naturally processed and presented in a time- and dose-dependent fashion up to 8 days after the start of DAC treatment, and converted the cell lines susceptible to antigen-specific recognition by CD8+ T-cell clones. In conclusion, NY-ESO-1 and numerous other CTAs localized on the X-chromosome are readily and transiently derepressed in AML cell lines treated with DAC. The susceptibility of DAC-treated AML cell lines to antigen-specific T-cell recognition has clear implications for future clinical trials combining DAC and specific immunotherapy in AML.

Conteduca G, Ferrera F, Pastorino L, et al.
The role of AIRE polymorphisms in melanoma.
Clin Immunol. 2010; 136(1):96-104 [PubMed] Related Publications
Polymorphisms of AIRE, a transcription factor that up-regulates intrathymic expression of tissue-specific antigens including melanoma-associated antigens (MAAs), may variably affect the selection of MAAs-specific thymocytes, generating T-cell repertoires protecting or predisposing individuals to melanoma. We found that AIRE single nucleotide polymorphisms (SNPs) rs1055311, rs1800520 and rs1800522 were significantly more frequent in healthy subjects than in melanoma patients, independently from sex, age and stages of melanoma. The presence of these SNPs was associated with increased frequency of two T-cell clonotypes specific for MAGE-1 linking their protective effect to selection/expansion of MAA-specific T cells. Interestingly, mRNA transcribed on the rs1800520 SNP showed increased free energy than the wild type suggesting that its reduced stability may be responsible for the different activity of the polymorphic AIRE molecule. This finding may contribute at identifying subjects with increased risk of developing melanoma or patients with melanoma that may take benefit from immunotherapy.

Tellez CS, Shen L, Estécio MR, et al.
CpG island methylation profiling in human melanoma cell lines.
Melanoma Res. 2009; 19(3):146-55 [PubMed] Related Publications
A better understanding of key molecular changes during the pathogenesis of melanoma could impact strategies to reduce mortality from this cancer. Two epigenetic events involved in the pathogenesis of cancer are hypermethylation of tumor-suppressor gene promoters associated with transcriptional repression and hypomethylation associated with gene reexpression and genomic instability. We analyzed 16 melanoma cell lines for aberrant hypermethylation of 15 cancer-linked genes (ER alpha, MGMT, RAR beta 2, RIL, RASSF1A, PAX7, PGR beta, PAX2, NKX2-3, OLIG2, HAND1, ECAD, CDH13, MLH1, and p16) and hypomethylation of two genes (MAGEA1, maspin) and two repetitive sequences (LINE-1 and Alu) using pyrosequencing. We observed hypermethylation of ER alpha in 50% of the cell lines, MGMT (50%), RAR beta 2 (44%), RIL (88%), RASSF1A (69%), PAX7 (31%), PGR beta (56%), PAX2 (38%), NKX2-3 (63%), OLIG2 (63%), HAND1 (63%), ECAD (88%), CDH13 (44%), MLH1 (0%), and p16 (6%). In human melanoma cell lines, hypomethylation of MAGEA1 (44%), maspin (25%), LINE-1 (75%), and Alu (13%) is frequently observed. We analyzed a panel of cell lines for BRAF V600E and NRAS codon 61 mutations. In melanoma cell lines, the BRAF and NRAS mutations had no association with aberrant methylation. We found that the cumulative aberrant hypermethylation of the gene promoters was correlated with the level of global DNA methylation. We conclude that aberrant hypermethylation, is frequent in melanoma cell lines, directly correlated with global DNA methylation, and independent of BRAF and NRAS mutations.

Aparicio A, North B, Barske L, et al.
LINE-1 methylation in plasma DNA as a biomarker of activity of DNA methylation inhibitors in patients with solid tumors.
Epigenetics. 2009; 4(3):176-84 [PubMed] Free Access to Full Article Related Publications
Multiple clinical trials are investigating the use of the DNA methylation inhibitors azacitidine and decitabine for the treatment of solid tumors. Clinical trials in hematological malignancies have shown that optimal activity does not occur at their maximum tolerated doses but selection of an optimal biological dose and schedule for use in solid tumor patients is hampered by the difficulty of obtaining tumor tissue to measure their activity. Here we investigate the feasibility of using plasma DNA to measure the demethylating activity of the DNA methylation inhibitors in patients with solid tumors. We compared four methods to measure LINE-1 and MAGE-A1 promoter methylation in T24 and HCT116 cancer cells treated with decitabine treatment and selected Pyrosequencing for its greater reproducibility and higher signal to noise ratio. We then obtained DNA from plasma, peripheral blood mononuclear cells, buccal mucosa cells and saliva from ten patients with metastatic solid tumors at two different time points, without any intervening treatment. DNA methylation measurements were not significantly different between time point 1 and time point 2 in patient samples. We conclude that measurement of LINE-1 methylation in DNA extracted from the plasma of patients with advanced solid tumors, using Pyrosequencing, is feasible and has low within patient variability. Ongoing studies will determine whether changes in LINE-1 methylation in plasma DNA occur as a result of treatment with DNA methylation inhibitors and parallel changes in tumor tissue DNA.

Akiyama Y, Maruyama K, Tai S, et al.
Characterization of a MAGE-1-derived HLA-A24 epitope-specific CTL line from a Japanese metastatic melanoma patient.
Anticancer Res. 2009; 29(2):647-55 [PubMed] Related Publications
A MAGE-1 HLA-A24 peptide-specific CTL line was characterized using a novel staining approach in the case of a metastatic melanoma patient who exhibited a remarkable clinical response in HLA-A24 peptide cocktail-pulsed dendritic cell (DCs) vaccine therapy. Briefly, pre- or post-vaccine peripheral blood mononuclear cells (PBMCs) from the vaccinated patient were stimulated several times with MAGE-1 A24 peptide-pulsed DCs and T2-A24 cells in vitro. Expanded MAGE-1 A24-specific CTL line was investigated in terms of immunological functions. The proportion of MAGE-1 A24 tetramer+ CTLs increased from 0.04% to 18.6%, and the absolute numbers of MAGE-1 tetramer+ CTLs increased up to 5,068-fold after stimulations. Expanded CTL line exhibited a strong cytotoxic activity against MAGE-1+ cancer cell line in the restriction of HLA. Finally, successful identification of MAGE-1 A24 peptide-specific T-cell receptor (TCR) cDNA from anti-TCR MoAbsorted CTL was obtained for the first time and the specific cytotoxicity in TCR gene-transduced naive T-cells was confirmed.

Vourc'h-Jourdain M, Volteau C, Nguyen JM, et al.
Melanoma gene expression and clinical course.
Arch Dermatol Res. 2009; 301(9):673-9 [PubMed] Related Publications
Evidence for the in vitro lymphocyte response against autologous melanoma has been accumulating over the past 10 years, leading to the identification of numerous melanoma-associated antigens recognised by T cells. These antigens are targets for specific immunotherapy protocols. However, their expression is heterogeneous during tumour progression and may contribute to therapeutic escape mechanisms and disease progression. This study was designed to chart the importance of these escape mechanisms, and to assess the relationship between gene expression and the clinical profile (especially survival data) of patients with melanoma. We studied the expression of certain melanoma genes in tissue biopsies from 202 patients using reverse transcriptase-polymerase chain reaction (RT-PCR). The evaluated genes were Melan-A, tyrosinase, Na-17A, MAGE-1, MAGE-3 and Ny-ESO-1. We then correlated the results to the patients' survival data. 202 samples (cutaneous, nodal and visceral biopsies) were analysed by RT-PCR. No relationship was found between clinical data and gene expression. No relationship was found between survival data and gene expression, when samples of all stages were combined in the analysis. However, interactions between gene expression and disease stage were significant. When stage III samples alone were considered, MAGE-3 expression alone or in association with the expression of the other tumour-specific genes was found to be significantly associated with a higher disease-free survival (respectively, P = 0.0349; 0.007). Our results provided no evidence for a relationship between gene expression and clinical data, or between gene expression and survival data. However, with regard to certain sub-groups, such as stage III samples, tumour gene expression was significantly associated with survival.

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