Research IndicatorsGraph generated 13 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MAGEA4 (cancer-related)
CD133 and cancer-testis antigens (CTAs) may be potential predicted markers of adjuvant chemotherapy or immune therapy, and they may be the independent prognostic factor of NSCLC. Nowadays, there is still no predictive biomarker identified for the use of adjuvant chemotherapy in non-small cell lung cancer (NSCLC) patients. To clarify the role of CD133 and CTAs as a predictive marker for adjuvant chemotherapy or prognostic factors of overall survival, we performed a retrospective study in 159 stage Ib-IIIA NSCLC patients receiving adjuvant chemotherapy or observe from April 2003 to March 2004 in our institute. Clinical data and gene anaylisis results were collected, while CD133 and three CTAs (MAGE-A4, NY-ESO-1, MAGE-A10) were determined according to their monoclonal antibodies such as CD133, 57B, D8.38 and 3GA11 by immunohistochemistry. All CTAs were more frequently expressed in squamous cell carcinoma (SCC) (50.0%, 26.9%, 34.6%) than in adenocarcinoma (16.2%, 16.2%, 16.2%). CD133 was more frequently found in patients with adenocarcinoma (P=0.044). Negative expression of CD133 was associated with a significantly longer overall survival compared to positive expression of CD133 (62.5 vs. 48.5 months, P=0.035). When combined with MAGEA4, NY-ESO-1or MAGE-A10, patients' OS showed significantly difference among different combination. (CD133-MAGEA4-/CD133-MAGEA4+/CD133+MAGEA4-/CD133+MAGEA4+: 65.6 months vs.51.5 months vs.32.2 months vs.19.8 months, P=0.000, CD133-NY-ESO-1-/ CD133+NY-ESO-1-/CD133-NY-ESO-1+/ CD133+NY-ESO-1+: 57.8 months vs. 55.7 months vs. 44.6 months vs. 28.5 months, P=0.000, CD133-MAGEA10-/CD133+ MAGEA10-/CD133-MAGEA10-/CD133+MAGEA10+: 66.2 months vs. 57.2 months vs. 48.8 months vs. 41.4 months, P=0.001). There is no difference between patients received adjuvant chemotherapy or not, but subgroup analysis showed that the patients with CD133+NY-ESO-1+ expression who received chemotherapy will survive longer than not receive adjuvant chemotherapy (received vs. not received, 52.1 vs. 27.1 months, P=0.020). In the subgroup with EGFR mutation/ALK translocation/Ros1 translocation/Ret fusion, the trend remained but without a statistically significant difference. Multivariate COX regression analysis showed that stage, CD133, CD133-MAGEA4- and CD133-NY-ESO-1- are independent prognostic factors. In conclusion, CTAs (MAGE-A4, NY-ESO-1, MAGE-A10) were more likely expressed in patients with squamous cell carcinoma and when CTAs combined with CD133, they can be better prognostic factors. Patients with CD133+NY-ESO-1+ expression may survive longer when treated with adjuvant chemotherapy, which indicates that the CD133 and CTAs might be a potential marker to guide adjuvant chemotherapy in this population.
Wang L, Xu Y, Luo C, et al.MAGEA10 gene expression in non-small cell lung cancer and A549 cells, and the affinity of epitopes with the complex of HLA-A(∗)0201 alleles.
Cell Immunol. 2015; 297(1):10-8 [PubMed
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MAGEA10, a cancer/testis antigens expressed in tumors but not in normal tissues with the exception of testis and placenta, represents an attractive target for cancer immunotherapy. However, suppressive cytoenvironment and requirement of specific HLA-alleles presentation frequently led to immunotherapy failure. In this study MAGEA10 was scarcely expressed in cancer patients, but enhanced by viili polysaccharides, which indicates a possibility of increasing epitopes presentation. Furthermore the correlation of gene expression with methylation, indicated by R(2) value for MAGEA10 that was 3 times higher than the value for other MAGE genes tested, provides an explanation of why MAGEA10 was highly inhibited, this is also seen by Kaplan-Meier analysis because MAGEA10 did not change the patients' lifespan. By using Molecular-Docking method, 3 MAGEA10 peptides were found binding to the groove position of HLA-A(∗)0210 as same as MAGEA4 peptide co-crystallized with HLA-A(∗)0210, which indicates that they could be promising for HLA-A(∗)0201 presentation in immunotherapy.
Ikeda H, Shiku HAdoptive immunotherapy of cancer utilizing genetically engineered lymphocytes.
Cancer Immunol Immunother. 2015; 64(7):903-9 [PubMed
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It is becoming increasingly clear that adoptive immunotherapy with genetically engineered T cells has the potential to control and even cure cancer in some patients. On the other hand, severe adverse events associated with efficacy have frequently been reported in clinical trials. Current and near-future challenges for the development of adoptive immunotherapy of cancer using genetically engineered T cells include minimization and prediction of adverse events; identification of new and effective targets, including patient-specific mutations; improvement in T cell functionality, persistence, and memory formation capacity; and utilization of allogeneic or cell line-based T cells.
Kageyama S, Ikeda H, Miyahara Y, et al.Adoptive Transfer of MAGE-A4 T-cell Receptor Gene-Transduced Lymphocytes in Patients with Recurrent Esophageal Cancer.
Clin Cancer Res. 2015; 21(10):2268-77 [PubMed
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PURPOSE: Preparative lymphodepletion, the temporal ablation of the immune system, has been reported to promote persistence of transferred cells along with increased rates of tumor regression in patients treated with adoptive T-cell therapy. However, it remains unclear whether lymphodepletion is indispensable for immunotherapy with T-cell receptor (TCR) gene-engineered T cells.
EXPERIMENTAL DESIGN: We conducted a first-in-man clinical trial of TCR gene-transduced T-cell transfer in patients with recurrent MAGE-A4-expressing esophageal cancer. The patients were given sequential MAGE-A4 peptide vaccinations. The regimen included neither lymphocyte-depleting conditioning nor administration of IL2. Ten patients, divided into 3 dose cohorts, received T-cell transfer.
RESULTS: TCR-transduced cells were detected in the peripheral blood for 1 month at levels proportional to the dose administered, and in 5 patients they persisted for more than 5 months. The persisting cells maintained ex vivo antigen-specific tumor reactivity. Despite the long persistence of the transferred T cells, 7 patients exhibited tumor progression within 2 months after the treatment. Three patients who had minimal tumor lesions at baseline survived for more than 27 months.
CONCLUSIONS: These results suggest that TCR-engineered T cells created by relatively short-duration in vitro culture of polyclonal lymphocytes in peripheral blood retained the capacity to survive in a host. The discordance between T-cell survival and tumor regression suggests that multiple mechanisms underlie the benefits of preparative lymphodepletion in adoptive T-cell therapy.
BACKGROUND: One of the two copies of the X chromosome is randomly inactivated in females as a means of dosage compensation. Loss of X chromosome inactivation (XCI) is observed in breast and ovarian cancers, and is frequent in basal-like subtype and BRCA1 mutation-associated breast cancers. We investigated the clinical implications of the loss of XCI in ovarian cancer and the association between the loss of XCI and BRCA1 dysfunction.
MATERIALS AND METHODS: We used open source data generated by The Cancer Genome Atlas (TCGA) Genome Data Analysis Centers. Ward's hierarchical clustering method was used to classify the methylation status of the X chromosome.
RESULTS: We grouped 584 high grade serous ovarian adenocarcinomas (HG-SOA) according to methylation status, loss of heterozygosity and deletion or gain of X chromosome into the following five groups: preserved inactivated X chromosome (Xi) group (n = 175), partial reactivation of Xi group (n = 100), p arm deletion of Xi group (n = 35), q arm deletion of Xi group (n = 44), and two copies of active X group (n = 230). We found four genes (XAGE3, ZNF711, MAGEA4, and ZDHHC15) that were up-regulated by loss of XCI. HG-SOA with loss of XCI showed aggressive behavior (overall survival of partial reactivation of Xi group: HR 1.7, 95% CI 1.1-2.5, two copies of active X group: HR 1.4, 95% CI 1.0-1.9). Mutation and hypermethylation of BRCA1 were not frequent in HG-SOA with loss of XCI.
CONCLUSIONS: Loss of XCI is common in HG-SOA and is associated with poor clinical outcome. The role of BRCA1 in loss of XCI might be limited. XCI induced aberrant expression of cancer-testis antigens, which may have a role in tumor aggressiveness.
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
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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 B220.127.116.11 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.
BACKGROUND: Melanoma antigen gene family (MAGE)-A4, a member of the cancer testis antigen family, has been reported in various cancers including melanoma, bladder, head and neck, oral, and lung, and is a potential target for T-cell-receptor-based immunotherapy. Baseline expression levels of the MAGE-A4 gene in thyroid cancer cell lines have not been previously studied thoroughly.
METHODS: Human thyroid cancer cell lines (8505c, HTh7, BCPAP, and TPC-1) were treated with either 10 μmol/L 5'-azacytidine (Aza) or 10 μmol/L 5-AZA-2'deoxycytidine (DAC) and evaluated for various MAGEA gene expression. Later melanoma cell lines A375 and 8505c were treated with PLX4720 in combination with DAC and evaluated for MAGE-A4 expression.
RESULTS: Only BCPAP cells expressed moderate levels of MAGE-A3 and MAGE-A6 at baseline. Treatment with DAC/Aza induced the expression of MAGE-A4 and MAGE-A1 in 8505c cells. PLX4720 treatment did not affect MAGE-A4 expression in 8505c cells, but increased its expression in A375 cells. In contrast, addition of PLX4720 to DAC-treated 8505c cells decreased the previously induced MAGE-A4 expression by DAC in these cells. A similar decrease in MAGE-A4 expression by DAC was also seen in 8505cBRAF(-/-) cells. Although DAC treatment resulted in demethylation of the MAGE-A4 promoter in 2 CpG sites, PLX addition to DAC did not affect the demethylation status.
CONCLUSION: Demethylating agents increased the expression of MAGE genes in thyroid cancer cells. The effect of BRAFV600E inhibitors on MAGE-A4 expression suggest the role of downstream MEK/BRAF signaling in its expression apart from promoter demethylation being the sole requirement. Expression of MAGE-A4 may make immunotherapeutic intervention possible in selected patients with thyroid cancer.
Bode PK, Thielken A, Brandt S, et al.Cancer testis antigen expression in testicular germ cell tumorigenesis.
Mod Pathol. 2014; 27(6):899-905 [PubMed
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Cancer testis antigens are encoded by germ line-associated genes that are present in normal germ cells of testis and ovary but not in differentiated tissues. Their expression in various human cancer types has been interpreted as 're-expression' or as intratumoral progenitor cell signature. Cancer testis antigen expression patterns have not yet been studied in germ cell tumorigenesis with specific emphasis on intratubular germ cell neoplasia unclassified as a precursor lesion for testicular germ cell tumors. Immunohistochemistry was used to study MAGEA3, MAGEA4, MAGEC1, GAGE1 and CTAG1B expression in 325 primary testicular germ cell tumors, including 94 mixed germ cell tumors. Seminomatous and non-seminomatous components were separately arranged and evaluated on tissue microarrays. Spermatogonia in the normal testis were positive, whereas intratubular germ cell neoplasia unclassified was negative for all five CT antigens. Cancer testis antigen expression was only found in 3% (CTAG1B), 10% (GAGE1, MAGEA4), 33% (MAGEA3) and 40% (MAGEC1) of classic seminoma but not in non-seminomatous testicular germ cell tumors. In contrast, all spermatocytic seminomas were positive for cancer testis antigens. These data are consistent with a different cell origin in spermatocytic seminoma compared with classic seminoma and support a progression model with loss of cancer testis antigens in early tumorigenesis of testicular germ cell tumors and later re-expression in a subset of seminomas.
Yamada R, Takahashi A, Torigoe T, et al.Preferential expression of cancer/testis genes in cancer stem-like cells: proposal of a novel sub-category, cancer/testis/stem gene.
Tissue Antigens. 2013; 81(6):428-34 [PubMed
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Cancer/testis (CT) antigens encoded by CT genes are immunogenic antigens, and the expression of CT gene is strictly restricted to only the testis among mature organs. Therefore, CT antigens are promising candidates for cancer immunotherapy. In a previous study, we identified a novel CT antigen, DNAJB8. DNAJB8 was found to be preferentially expressed in cancer stem-like cells (CSCs)/cancer-initiating cells (CICs), and it is thus a novel CSC antigen. In this study, we hypothesized that CT genes are preferentially expressed in CSCs/CICs rather than in non-CSCs/-CICs and we examined the expression of CT genes in CSCs/CICs. The expression of 74 CT genes was evaluated in side population (SP) cells (=CSC) and main population (MP) cells (=non-CSC) derived from LHK2 lung adenocarcinoma cells, SW480 colon adenocarcinoma cells and MCF7 breast adenocarcinoma cells by RT-PCR and real-time PCR. Eighteen genes (MAGEA2, MAGEA3, MAGEA4, MAGEA6, MAGEA12, MAGEB2, GAGE1, GAGE8, SPANXA1, SPANXB1, SPANXC, XAGE2, SPA17, BORIS, PLU-1, SGY-1, TEX15 and CT45A1) showed higher expression levels in SP cells than in MP cells, whereas 10 genes (BAGE1, BAGE2, BAGE4, BAGE5, XAGE1, LIP1, D40, HCA661, TDRD1 and TPTE) showed similar expression levels in SP cells and MP cells. Thus, considerable numbers of CT genes showed preferential expression in CSCs/CICs. We therefore propose a novel sub-category of CT genes in this report: cancer/testis/stem (CTS) genes.
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
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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.
BACKGROUND: L1CAM was originally identified as an adhesion molecule involved in neural development. In many human carcinomas L1CAM is over-expressed and is associated with a bad prognosis. We previously reported that L1CAM was absent in the vast majority of endometrioid endometrial carcinomas (ECs) (type 1) but was strongly expressed in the more aggressive serous and clear-cell ECs (termed type 2). The differential regulation of L1CAM in ECs is not well understood. Recent evidence suggests that it can be regulated by epigenetic mechanisms. Here we investigated the role of DNA-methylation of the L1CAM promoter for expression. We also studied the relationship to cancer testis (CT-X) antigens that co-localize with L1CAM on chromosome Xq28, a region that is often activated in human tumors.
METHODS: We used EC cell lines and primary tumor tissues for our analysis. For expression analysis we employed RT-PCR and Western blotting. DNA-Methylation of the L1CAM promoter was determined after bisulfite conversation and DNA sequencing. Tumor tissues were examined by immunohistochemical (IHC) staining.
RESULTS: We demonstrate that the treatment of L1CAM low/negative expressing EC cell lines with 5'-Azacytidine (5-AzaC) or knock-down of DNMT1 (DNA methyltransferase 1) as well as the HDAC (histone deacetylase) inhibitor Trichostatin A (TSA) up-regulated L1CAM at the mRNA and protein level. The L1CAM gene has two promoter regions with two distinct CpG islands. We observed that the expression of L1CAM correlated with hypermethylation in promoter 1 and 5-AzaC treatment affected the DNA-methylation pattern in this region. The CT-X antigens NY-ESO-1, MAGE-A3 and MAGE-A4 were also strongly up-regulated by 5-AzaC or knock-down of DNMT1 but did not respond to treatment with TSA. Primary EC tumor tissues showed a variable methylation pattern of the L1CAM promoter. No striking differences in promoter methylation were observed between tumor areas with L1CAM expression and those without expression.
CONCLUSIONS: L1CAM expression correlated with methylation of the L1CAM promoter in EC cell lines. In negative cell lines L1CAM expression is up-regulated by epigenetic mechanism. Although genes localized on Xq28 are often re-expressed by human tumors, L1CAM and CT-X antigens show distinct regulation in response to HADC inhibitors and 5-AzaC.
Cabezón T, Gromova I, Gromov P, et al.Proteomic profiling of triple-negative breast carcinomas in combination with a three-tier orthogonal technology approach identifies Mage-A4 as potential therapeutic target in estrogen receptor negative breast cancer.
Mol Cell Proteomics. 2013; 12(2):381-94 [PubMed
] Free Access to Full Article Related Publications
Breast cancer is a very heterogeneous disease, encompassing several intrinsic subtypes with various morphological and molecular features, natural history and response to therapy. Currently, molecular targeted therapies are available for estrogen receptor (ER)(-) and human epidermal growth factor receptor 2 (Her2)-positive breast tumors. However, a significant proportion of primary breast cancers are negative for ER, progesterone receptor (PgR), and Her2, comprising the triple negative breast cancer (TNBC) group. Women with TNBC have a poor prognosis because of the aggressive nature of these tumors and current lack of suitable targeted therapies. As a consequence, the identification of novel relevant protein targets for this group of patients is of great importance. Using a systematic two dimensional (2D) gel-based proteomic profiling strategy, applied to the analysis of fresh TNBC tissue biopsies, in combination with a three-tier orthogonal technology (two dimensional PAGE/silver staining coupled with MS, two dimensional Western blotting, and immunohistochemistry) approach, we aimed to identify targetable protein markers that were present in a significant fraction of samples and that could define therapy-amenable sub-groups of TNBCs. We present here our results, including a large cumulative database of proteins based on the analysis of 78 TNBCs, and the identification and validation of one specific protein, Mage-A4, which was expressed in a significant fraction of TNBC and Her2-positive/ER negative lesions. The high level expression of Mage-A4 in the tumors studied allowed the detection of the protein in the tumor interstitial fluids as well as in sera. The existence of immunotherapeutics approaches specifically targeting this protein, or Mage-A protein family members, and the fact that we were able to detect its presence in serum suggest novel management options for TNBC and human epidermal growth factor receptor 2 positive/estrogen receptor negative patients bearing Mage-A4 positive tumors.
Baba T, Shiota H, Kuroda K, et al.Clinical significance of human leukocyte antigen loss and melanoma-associated antigen 4 expression in smokers of non-small cell lung cancer patients.
Int J Clin Oncol. 2013; 18(6):997-1004 [PubMed
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BACKGROUND: Melanoma-associated antigen-A4 (MAGE-A4) is one of the candidates for a target of immunotherapy and is expressed in non-small cell lung cancer (NSCLC). However, tumors sometimes lose human leukocyte antigen (HLA) class I expression, and tumor-specific T cells cannot eliminate the tumor with loss of HLA. However, the relationship between MAGE-A4 expression and HLA loss has remained unclear.
METHODS: Among 363 NSCLC patients who consecutively underwent curative surgery, 187 cases whose material could be analyzed were reviewed. The expression of HLA class I molecules was assessed by immunohistochemical staining. The expression of MAGE-A4 was analyzed by RT-PCR.
RESULTS: Seventy-seven tumors expressed HLA normally; however, 110 tumors lost HLA. The proportion of patients with a smoking habit and expressing the MAGE-A4 gene in patients with HLA loss was higher than those with HLA expression (p = 0.04 and 0.028, respectively). Five-year overall survival (OS) rate in the patients expressing MAGE-A4 but with loss of HLA was 52.4 %, and OS was significantly poorer than their counterparts (74.0 %, p = 0.036). Multivariate analysis indicated that advanced stage or history of smoking and HLA loss was an independently poor prognostic predictor of OS in NSCLC (p < 0.01 and p = 0.04, respectively).
CONCLUSION: HLA class I loss in NSCLC was related to smoking history and MAGE-A4 expression of tumors. HLA class I loss in smokers or patients with the MAGE-A4 gene was a prognostic factors in NSCLC.
While the expression of genes that are normally involved in spermatogenesis is frequently detected in tumors, the extent to which these gene products are required for neoplastic behaviors is unclear. To begin to address their functional relevance to tumorigenesis, we identified a cohort of proteins which display synthetic lethality with paclitaxel in non-small-cell lung cancer and whose expression is biased toward testes and tumors. Remarkably, these testis proteins, FMR1NB, NXF2, MAGEA5, FSIP1, and STARD6, are required for accurate chromosome segregation in tumor cells. Their individual depletion enhances the generation of multipolar spindles, increases mitotic transit time, and induces micronucleation in response to an otherwise innocuous dose of paclitaxel. The underlying basis for abnormal mitosis is an alteration in microtubule function, as their depletion increases microtubule cytaster formation and disrupts microtubule stability. Given these observations, we hypothesize that reactivated testis proteins may represent unique tumor cell vulnerabilities which, if targeted, could enhance responsiveness to antimitotic therapy. Indeed, we demonstrate that combining paclitaxel with a small-molecule inhibitor of the gametogenic and tumor cell mitotic protein TACC3 leads to enhanced centrosomal abnormalities, activation of death programs, and loss of anchorage-independent growth.
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
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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.
Baba T, Shiota H, Kuroda K, et al.Cancer/testis antigen expression as a predictor for epidermal growth factor receptor mutation and prognosis in lung adenocarcinoma.
Eur J Cardiothorac Surg. 2013; 43(4):759-64 [PubMed
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OBJECTIVES: Immune therapy targeting cancer/testis (CT) antigens improve the survival in several types of solid tumours. The expression of CT antigens is related to poor survival in non-small-cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) mutation is the best predictive factor for the sensitivity to tyrosine kinase inhibitors in lung adenocarcinoma. The aim of this study was to elucidate the correlation between the expression of CT antigens and clinicopathological factors, including the EGFR mutation, and to analyse the prognosis in lung adenocarcinoma.
METHODS: Data were collected from a total of 281 lung adenocarcinoma patients who underwent surgery. Among them, 125 cases, whose specimens were too small to extract sufficient DNA and/or RNA, and 2 cases with the coexistence of another histological lung cancer were excluded. A total of 154 patients were reviewed. The expression of CT antigens (melanoma-associated antigen gene [MAGE]-A4 and KK-LC-1) and the EGFR-activating mutation (L858R point mutation in exon 21 and inframe deletion in exon 19) was evaluated by using polymerase chain reaction amplification.
RESULTS: The expression of MAGE-A4 and KK-LC-1 was detected in 14 (9%) and 54 patients (35%) with adenocarcinoma. The EGFR-activating mutation was found in 64 patients (42%). Univariate and multivariate analyses demonstrated that tumours expressing at least one CT antigen were associated with no EGFR mutation (odds ratio = 0.3; 95% confidence interval, 0.14-0.71; P < 0.01). A survival analysis was performed in 135 patients who underwent complete resection and the 5-year overall survival rate was 71.1% in those with any expression of CT antigens and 83.2% in those without expression of the genes (P < 0.04).
CONCLUSION: Two different therapeutic targets, EGFR-activating mutation and CT antigen, have a negative relationship with each other.
Hussein YM, Morad FE, Gameel MA, et al.MAGE-4 gene m-RNA and TGF in blood as potential biochemical markers for HCC in HCV-infected patients.
Med Oncol. 2012; 29(5):3055-62 [PubMed
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Progression from chronic hepatitis C virus infection to cirrhosis then to hepatocellular carcinoma usually results in some protein changes in peripheral blood. We evaluated MAGE-4 mRNA, TGFβ1 and AFP in peripheral blood as potential biochemical markers for diagnosis and prognosis of some complications of HCV infection. MAGE-4 mRNA in blood by reverse transcription polymerase chain reaction, serum TGF-Β1 and AFP by ELISA was assayed in seventy-five individuals who were classified into five groups: group I (control) comprised fifteen apparently healthy volunteers, group II involved fifteen HCV-infected patients without cirrhosis, group III involved fifteen HCV fifteen HCV-infected patients with cirrhosis, group IV included fifteen HCV-infected patients with cirrhosis and early stage HCC, and group V included fifteen HCV cirrhotic patients and late-stage HCC. We found that the frequency of positivity of MAGE-4 among the late hepatoma group was 40 %, while in the early hepatoma group the positivity was 6.7 %. The results for TGF-Β1 revealed a significant increase in serum TGF-Β1 in groups IV and V as compared to control, II, III groups. The obtained results of AFP showed a significant positive increase in serum AFP in groups IV and V when compared to groups II and III. Detection of MAGE-4 transcripts in blood, especially with follow-up survey, may help to predict the prognosis and monitoring of the response to the therapy, and serum TGF-Β1 level in HCC patients is directly correlated with metastasis and recurrence of tumors and increases gradually with the progression of HCC.
Park JH, Do NY, Han SI, Lim SCUsefulness 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
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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.
Nishikawa H, Maeda Y, Ishida T, et al.Cancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma.
Blood. 2012; 119(13):3097-104 [PubMed
] Related Publications
Adult T-cell leukemia/lymphoma (ATLL) is an intractable hematologic malignancy caused by human T-lymphotropic virus type 1 (HTLV-1), which infects approximately 20 million people worldwide. Here, we have explored the possible expression of cancer/testis (CT) antigens by ATLL cells, as CT antigens are widely recognized as ideal targets of cancer immunotherapy against solid tumors. A high percentage (87.7%) of ATLL cases (n = 57) expressed CT antigens at the mRNA level: NY-ESO-1 (61.4%), MAGE-A3 (31.6%), and MAGE-A4 (61.4%). CT antigen expression was confirmed by immunohistochemistry. This contrasts with other types of lymphoma or leukemia, which scarcely express these CT antigens. Humoral immune responses, particularly against NY-ESO-1, were detected in 11.6% (5 of 43) and NY-ESO-1-specific CD8(+) T-cell responses were observed in 55.6% (5 of 9) of ATLL patients. NY-ESO-1-specific CD8(+) T cells recognized autologous ATLL cells and produced effector cytokines. Thus, ATLL cells characteristically express CT antigens and therefore vaccination with CT antigens can be an effective immunotherapy of ATLL.
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
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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.
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.
Montoro JR, Mamede RC, Neder Serafini L, et al.Expression of cancer-testis antigens MAGE-A4 and MAGE-C1 in oral squamous cell carcinoma.
Head Neck. 2012; 34(8):1123-8 [PubMed
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BACKGROUND: Tumor markers are genes or their products expressed exclusively or preferentially in tumor cells and cancer-testis antigens (CTAs) form a group of genes with a typical expression pattern expressed in a variety of malignant neoplasms. CTAs are considered potential targets for cancer vaccines. It is possible that the CTA MAGE-A4 (melanoma antigen) and MAGE-C1 are expressed in carcinoma of the oral cavity and are related with survival.
METHODS: This study involved immunohistochemical analysis of 23 patients with oral squamous cell carcinoma (SCC) and was carried out using antibodies for MAGE-A4 and MAGE-C1. Fisher's exact test and log-rank test were used to evaluate the results.
RESULTS: The expression of the MAGE-A4 and MAGE-C1 were 56.5% and 47.8% without statistical difference in studied variables and survival.
CONCLUSION: The expression of at least 1 CTA was present in 78.3% of the patients, however, without correlation with clinicopathologic variables and survival.
Shirakura Y, Mizuno Y, Wang L, et al.T-cell receptor gene therapy targeting melanoma-associated antigen-A4 inhibits human tumor growth in non-obese diabetic/SCID/γcnull mice.
Cancer Sci. 2012; 103(1):17-25 [PubMed
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Adoptive cell therapy with lymphocytes that have been genetically engineered to express tumor-reactive T-cell receptors (TCR) is a promising approach for cancer immunotherapy. We have been exploring the development of TCR gene therapy targeting cancer/testis antigens, including melanoma-associated antigen (MAGE) family antigens, that are ideal targets for adoptive T-cell therapy. The efficacy of TCR gene therapy targeting MAGE family antigens, however, has not yet been evaluated in vivo. Here, we demonstrate the in vivo antitumor activity in immunodeficient non-obese diabetic/SCID/γc(null) (NOG) mice of human lymphocytes genetically engineered to express TCR specific for the MAGE-A4 antigen. Polyclonal T cells derived from human peripheral blood mononuclear cells were transduced with the αβ TCR genes specific for MAGE-A4, then adoptively transferred into NOG mice inoculated with MAGE-A4 expressing human tumor cell lines. The transferred T cells maintained their effector function in vivo, infiltrated into tumors, and inhibited tumor growth in an antigen-specific manner. The combination of adoptive cell therapy with antigen peptide vaccination enhanced antitumor activity, with improved multifunctionality of the transferred cells. These data suggest that TCR gene therapy with MAGE-A4-specific TCR is a promising strategy to treat patients with MAGE-A4-expressing tumors; in addition, the acquisition of multifunctionality in vivo is an important factor to predict the quality of the T-cell response during adoptive therapy with human lymphocytes.
PURPOSE: Patients with Hodgkin lymphoma (HL) relapsing after hematopoietic stem cell transplant have limited options for long-term cure. We have shown that infused cytotoxic T cells (CTL) targeting Epstein Barr virus (EBV)-derived proteins induced complete remissions in EBV(+) HL patients. A limitation of this approach is that up to 70% of relapsed HL tumors are EBV-negative. For these patients, an alternative is to target the cancer/testis antigen MAGE-A4 present in EBV antigen-negative HL tumors. Furthermore, epigenetic modification by clinically available demethylating agents can enhance MAGE-A4 expression in previously MAGE-negative tumors.
EXPERIMENTAL DESIGN: We explored the feasibility of combining adoptive T cell therapy with epigenetic modification of tumor antigen expression. We further characterized MAGE-A4-specific T-cell phenotype and function, and examined the effects of the epigenetic modifying drug decitabine on these T cells.
RESULTS: Cytotoxic T cells were generated specifically recognizing MAGE-A4 expressed by autologous HL targets and tumor cell lines. Decitabine-previously shown to increase tumor antigen expression in HL-did not compromise MAGE-A4-specific T-cell phenotype and function. In patients treated with decitabine, expanded MAGE-A4-specific T cells had a broader antitumor T cell repertoire, consistent with increased antigen stimulation in vivo.
CONCLUSIONS: Adoptive transfer of MAGE-A4-specific T cells, combined with epigenetic modifying drugs to increase expression of the protein, may improve treatment of relapsed HL.
Forghanifard MM, Gholamin M, Farshchian M, et al.Cancer-testis gene expression profiling in esophageal squamous cell carcinoma: identification of specific tumor marker and potential targets for immunotherapy.
Cancer Biol Ther. 2011; 12(3):191-7 [PubMed
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Cancer-testis antigens (CTAs) are often specifically expressed in cancer cells and under normal conditions are only considered to be expressed in the germ line cells and the placenta. CTAs are potential targets for cancer immunotherapy and therefore necessitates their expression profiling. The expression profile of LAGE1, MAGE-A4 and NY-ESO1, their possible correlations and interaction, and the clinicopathological associations of each marker were studied. RNA was extracted from fresh esophagectomy tissues of 41 esophageal squamous cell carcinoma (ESCC) patients prior to any other therapeutic intervention. The relative mRNA expression of LAGE1, MAGE-A4 and NY-ESO1 was assessed with the real-time reverse transcription-polymerase chain reaction (RT-PCR) 5' nuclease assay. The overexpression of LAGE1, MAGE-A4 and NY-ESO1 was found in 39, 90.2 and 41.4% of ESCC samples respectively. Of the patients, 97.5% showed an overexpression of at least one CTA. The relative expression of MAGE-A4 was directly associated with lymph node metastasis and the stage of the tumor (p < 0.05). A significant direct correlation was also detected between the MAGE-A4/LAGE1 and MAGE-A4/NY-ESO1 levels of gene expression. MAGE-A4 is identified as a specific biomarker of ESCC with a possible oncogenic role contributing to tumor progression. Interactions between MAGE-A4, LAGE1 and NY-ESO1 and their significant clinical consequences introduce these CTAs as appropriate targets for a polyvalent cancer vaccine.
Bhan S, Negi SS, Shao C, et al.BORIS binding to the promoters of cancer testis antigens, MAGEA2, MAGEA3, and MAGEA4, is associated with their transcriptional activation in lung cancer.
Clin Cancer Res. 2011; 17(13):4267-76 [PubMed
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PURPOSE: Aim of this study was to determine whether BORIS (Brother of the Regulator of Imprinted Sites) is a regulator of MAGEA2, MAGEA3, and MAGEA4 genes in lung cancer.
EXPERIMENTAL DESIGN: Changes in expression of MAGEA genes upon BORIS induction/knockdown were studied. Recruitment of BORIS and changes in histone modifications at their promoters upon BORIS induction were analyzed. Luciferase assays were used to study their activation by BORIS. Changes in methylation at these promoters upon BORIS induction were evaluated.
RESULTS: Alteration of BORIS expression by induction/knockdown directly correlated with expression of MAGEA genes. BORIS was enriched at their promoters in H1299 cells, which show high expression of these cancer testis antigens (CTA), compared with normal human bronchial epithelial (NHBE) cells which show low expression of the target CTAs. BORIS induction in A549 cells resulted in increased amounts of BORIS and activating histone modifications at their promoters along with a corresponding increase in their expression. Similarly, BORIS binding at these promoters in H1299 correlates with enrichment of activating modifications, whereas absence of BORIS binding in NHBE is associated with enrichment of repressive marks. BORIS induction of MAGEA3 was associated with promoter demethylation, but no methylation changes were noted with activation of MAGEA2 and MAGEA4.
CONCLUSIONS: These data suggest that BORIS positively regulates these CTAs by binding and inducing a shift to a more open chromatin conformation with promoter demethylation for MAGEA3 or independent of promoter demethylation in case of MAGEA2 and MAGEA4 and may be a key effector involved in their derepression in lung cancer.
In the present study we analyzed immunohistochemical expression of MAGE-A 3/4 and NY-ESO-1 in 55 samples of esophageal squamous cell carcinomas (ESCC) and their respective lymph node metastases. To our knowledge this is the first study to assess and compare the expression of these antigens in ESCC lymph node metastases. Fifty (90.9%) primary ESCC were positive for MAGE-A 3/4 and 53 (96.6%) were positive for NY-ESO-1. MAGE-A 3/4 was expressed in all lymph node metastases and the intensity of expression was high in a majority of cases. NY-ESO-1 was negative in 2 (7.1%) lymph nodes metastases, while the reaction was predominantly moderate in the positive group. In primary tumors MAGE-A 3/4 showed a significantly higher intensity of expression compared to NY-ESO-1 (P=0.047), while in lymph node metastases the intensity of expression was not significantly different (P=0.387). Primary tumors with and without lymph node metastases showed no significant differences in MAGE-A 3/4 (P=0.672) and NY-ESO-1 (P=0.444) expression. Intensity of MAGE-A 3/4 (P=0.461) and NY-ESO-1 (P=0.414) expression in primary tumors was not significantly different compared to the expression in their respective lymph nodes metastases. Expression of MAGE-A 3/4 in primary tumors showed significant positive correlation with primary tumor expression of NY-ESO-1 (P=0.021) but no significant correlation with the expression of MAGE-A 3/4 in lymph node metastases (P=0.056). Expression of NY-ESO-1 in primary tumors showed significant positive correlation with the expression of NY-ESO-1 in lymph node metastases (P=0.001) and significant negative correlation with patients’ age (P<0.001). Expression of MAGE-A 3/4 and NY-ESO-1 in primary tumors and lymph node metastases showed no significant correlation with prognostic parameters such as tumor grade and TNM stage (P>0.05). We have shown different levels of MAGE-A 3/4 and NY-ESO-1 expression in almost all specimens of primary tumor and lymph node metastases, suggesting that ESCC may be possible target of immunotherapy and anti-tumor vaccination. High levels of expression in lymph node metastases indicate possible clinical benefit of postoperative vaccine with MAGE-A3 and NY-ESO-1 in advanced stage of disease.
Hussein YM, Ghareib AF, Mohamed RH, et al.MAGE-3 and MAGE-4 genes as possible markers for early detection of metastases in hepatitis C virus Egyptian patients complicated by hepatocellular carcinoma.
Med Oncol. 2012; 29(2):994-9 [PubMed
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The dissemination of hepatocellular carcinoma (HCC) cells into the circulation plays a critical role in post-operative recurrence and metastasis. Early detection of metastatic tumor cells is critical to identify HCC patients at high risk of relapse. MAGE-3 and -4 genes were evaluated by reverse transcription polymerase chain reaction for the possibility of using them as new markers for early detection of metastases in 160 chronic HCV Egyptian patients, 115 of them were complicated with HCC. The expressions of MAGE-3 and MAGE-4 mRNA in peripheral blood of patients with metastatic HCC were 36 and 52%, respectively. While the expressions of MAGE-3 and MAGE-4 mRNA in peripheral blood of patients with localized HCC were 12.5 and 15%, respectively. Moreover, at least one type of mRNA was found in the peripheral blood of 68% of the metastatic HCC patients and in 20% of the localized HCC patients. While neither the controls nor the cirrhotic patients show expression of MAGE-4 mRNA in their peripheral blood. MAGE-3 and MAGE-4 may be a promising diagnostic tool for monitoring the prognosis of HCC patients and early detection of occult hematogenous metastasis of HCC.
Hussein YM, Gharib AF, Etewa RL, et al.The melanoma-associated antigen-A3, -A4 genes: relation to the risk and clinicopathological parameters in breast cancer patients.
Mol Cell Biochem. 2011; 351(1-2):261-8 [PubMed
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This study aimed to evaluate the clinical reliability and accuracy of two MAGE transcripts (MAGE-A3, MAGE-A4 mRNA) in the peripheral blood (PB) of patients with breast cancer (BC), and to evaluate their potential limits and utility to detect BC. We aimed also to analyze their relation to clinicopathological characteristics of the tumor. This study is a prospective, controlled, double-blinded study conducted on 100 BC women and 100 age-matched control women. There were 52 patients with localized breast mass with no evidence of nodal affection or distant metastases and 48 patients suffering from metastatic BC. MAGE-A3 and MAGE-A4 mRNA in the PB were assayed using reverse transcriptase-polymerase chain reaction (RT-PCR). None of the control women was positive for either MAGE-A3, MAGE-A4. In BC women, positivity for MAGE-A3 in PB was observed in 37 patients (37%), and MAGE-A4 positivity was observed in 11 patients (11%); with 100% specificity for both transcripts. The presence of MAGE-A3 was significantly associated with nodal status (P = 0.009), tumor size (P = 0.009), and American Joint Committee on Cancer stage (P = 0.009), whereas MAGE-A4 positivity was significantly associated with histological grade (P = 0.020). RT-PCR assays of MAGE-A3 and MAGE-A4 in the PB of BC patients may have prognostic and predictive implications, and they are promising specific tumor markers of BC.
Melo DH, Mamede RC, Neder L, et al.Expression of MAGE-A4 and MAGE-C1 tumor-associated antigen in benign and malignant thyroid diseases.
Head Neck. 2011; 33(10):1426-32 [PubMed
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BACKGROUND: A subset of thyroid tumors characterized by a follicular growth pattern can represent a serious diagnosis. Immunohistochemistry and molecular pathology for genetic profiling have been used in an attempt to resolve some of these issues.
METHODS: Tumor tissue samples of thyroid were obtained from 70 patients who underwent surgical therapy. They were divided into 4 groups: 20 adenomatous goiters, 10 follicular adenomas, 24 papillary carcinomas, and 16 follicular carcinomas. Immunohistochemical analysis was carried out using antibodies for MAGE-A4 (melanoma antigen-encoding gene A4) and MAGE-C1 (melanoma antigen-encoding gene C1).
RESULTS: Standard histologic analysis and immunohistochemistry analysis of MAGE-A4 and MAGE-C1 expression were performed in all patients. The antigens examined were not expressed in any of the tissues.
CONCLUSIONS: The malignant degeneration of normal tissues is a multifactorial process, varying considerably both among tumor types and among individual patients. The present study showed that there was no immunolabeling of the MAGE-A4 and MAGE-C1 antigens.