GAGE1

Gene Summary

Gene:GAGE1; G antigen 1
Aliases: CT4.1, GAGE-1
Location:Xp11.23
Summary:This gene belongs to a family of genes that are expressed in a variety of tumors but not in normal tissues, except for the testis. The sequences of the family members are highly related but differ by scattered nucleotide substitutions. The antigenic peptide YRPRPRRY, which is also encoded by several other family members, is recognized by autologous cytolytic T lymphocytes. Nothing is presently known about the function of this protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:G antigen 1
Source:NCBIAccessed: 13 March, 2017

Ontology:

What does this gene/protein do?
GAGE1 is implicated in:
- cellular defense response
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

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 (9)

Latest Publications: GAGE1 (cancer-related)

Reardon ES, Hong JA, Straughan DM, et al.
Pulmonary Metastases Exhibit Epigenetic Clonality: Implications for Precision Cancer Therapy.
Ann Thorac Surg. 2015; 100(5):1839-48; discussion 1848 [PubMed] Related Publications
BACKGROUND: Development of effective cancer therapies may be limited by intratumoral heterogeneity, which facilitates outgrowth and organ-specific dissemination of treatment resistant clones. At present, limited information is available regarding epigenetic landscapes of pulmonary metastases. This study was undertaken to characterize epigenetic signatures of pulmonary metastases and to identify potential therapeutic targets.
METHODS: RNA and DNA were extracted from 65 pulmonary metastases resected from 12 patients (5 with sarcoma, 7 with adrenocortical carcinoma). Quantitative reverse transcription polymerase chain reaction techniques were used to evaluate expression levels of cancer-testis (CT) genes (NY-ESO-1, MAGE-A3, MAGE-A9, MAGE-A12, GAGE1, CT-45, SSX-1, and SSX-2), tumor suppressor (TS) genes (p16 and RASSF1A), and genes encoding epigenetic modifiers (DNMT1, DNMT3A, DNMT3B, EZH2, EED, and SUZ12), aberrantly expressed in human malignant diseases. Pyrosequencing techniques were used to quantitate DNA methylation levels in LINE1, NBL2, and D4Z4 repetitive sequences and promoter methylation status of differentially regulated genes. Results of these analyses were compared with a standardized panel of normal lung tissues.
RESULTS: Pulmonary metastases exhibited histologically related and patient-specific global DNA demethylation. Significant interpatient heterogeneity of gene expression was observed even among patients with similar tumor histologic features. Epigenetic signatures appeared consistent among metastases from the same patient, irrespective of the time of resection (synchronous/metachronous) or the anatomic location. EZH2, EED, and SUZ12 (core components of Polycomb repressive complex-2 [PRC-2]) were upregulated in the majority of metastases.
CONCLUSIONS: Pulmonary metastases exhibit patient-specific epigenetic clonality, which may be exploited for precision therapies targeting aberrant CT or TS gene expression. PRC-2 may be a shared target for epigenetic therapy of pulmonary metastases.

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] Related Publications
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] Related Publications
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.

Geng W, Ng KT, Sun CK, et al.
The role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in hepatocellular carcinoma.
PLoS One. 2011; 6(11):e27362 [PubMed] Free Access to Full Article Related Publications
AIMS: We previously demonstrated Proline rich tyrosine kinase 2 (Pyk2) plays important roles in regulating tumor progression, migration and invasion in hepatocellular carcinoma (HCC). In this study, we aimed to examine the role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in HCC and to explore its underlying molecular mechanism.
METHODOLOGY/PRINCIPAL FINDINGS: Stable transfectants either overexpressing or suppressing Pyk2 were established in different HCC cell lines. MTT, colony formation and Annexin-V assays were employed to examine their in vitro responses to cisplatin. Xenograft ectopic and orthotopic nude mice models were generated to investigate the in vivo responses of them to cisplatin treatment. cDNA microarray was performed to identify Pyk2-induced genes which were further validated by quantitative real-time RT-PCR using clinical HCC samples. In vitro functional study demonstrated that Pyk2-overexpressing HCC transfectants exhibited relatively lower cytotoxicity, higher colony-forming ability and lower apoptosis to cisplatin compared with the control transfectants. Moreover, Pyk2 overexpressing HCC transfectants had a higher survival rate under cisplatin treatment by up-regulation of AKT phosphorylation. In vivo xenograft nude mice model demonstrated that Pyk2-overexpressing transfectants developed higher tolerance to cisplatin treatment together with less tumor necrosis and apoptosis. cDNA microarray analysis revealed that there were more than 4,000 genes differentially expressed upon overexpression of Pyk2. Several upregulated genes were found to be involved in drug resistance and invasion in cancers. Among them, the expression profiles of MDR1, GAGE1, STAT1 and MAP7 were significantly associated with the expression of Pyk2 in clinical HCC samples.
CONCLUSIONS: Our results may suggest a new evidence of Pyk2 on promoting cisplatin resistance of HCC cells through preventing cell apoptosis, activation of AKT pathway and upregulation of drug resistant genes.

Cuffel C, Rivals JP, Zaugg Y, et al.
Pattern and clinical significance of cancer-testis gene expression in head and neck squamous cell carcinoma.
Int J Cancer. 2011; 128(11):2625-34 [PubMed] Related Publications
Cancer-testis (CT) antigens comprise families of tumor-associated antigens that are immunogenic in patients with various cancers. Their restricted expression makes them attractive targets for immunotherapy. The aim of this study was to determine the expression of several CT genes and evaluate their prognostic value in head and neck squamous cell carcinoma (HNSCC). The pattern and level of expression of 12 CT genes (MAGE-A1, MAGE-A3, MAGE-A4, MAGE-A10, MAGE-C2, NY-ESO-1, LAGE-1, SSX-2, SSX-4, BAGE, GAGE-1/2, GAGE-3/4) and the tumor-associated antigen encoding genes PRAME, HERV-K-MEL, and NA-17A were evaluated by RT-PCR in a panel of 57 primary HNSCC. Over 80% of the tumors expressed at least 1 CT gene. Coexpression of three or more genes was detected in 59% of the patients. MAGE-A4 (60%), MAGE-A3 (51%), PRAME (49%) and HERV-K-MEL (42%) were the most frequently expressed genes. Overall, the pattern of expression of CT genes indicated a coordinate regulation; however there was no correlation between expression of MAGE-A3/A4 and BORIS, a gene whose product has been implicated in CT gene activation. The presence of MAGE-A and NY-ESO-1 proteins was verified by immunohistochemistry. Analysis of the correlation between mRNA expression of CT genes with clinico-pathological characteristics and clinical outcome revealed that patients with tumors positive for MAGE-A4 or multiple CT gene expression had a poorer overall survival. Furthermore, MAGE-A4 mRNA positivity was prognostic of poor outcome independent of clinical parameters. These findings indicate that expression of CT genes is associated with a more malignant phenotype and suggest their usefulness as prognostic markers in HNSCC.

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.

Mishra DK, Chen Z, Wu Y, et al.
Global methylation pattern of genes in androgen-sensitive and androgen-independent prostate cancer cells.
Mol Cancer Ther. 2010; 9(1):33-45 [PubMed] Free Access to Full Article Related Publications
Promoter DNA methylation of CpG islands is an important epigenetic mechanism in cancer development. We have characterized the promoter methylation profile of 82 genes in three prostate cancer cell lines (LNCaP, PC3, and DU145) and two normal prostate cell lines (RWPE1 and RWPE2). The methylation pattern was analyzed using a Panomics gene array system that consists of immobilized probes of known gene promoters on a nitrocellulose membrane. Methylation binding protein-purified methylated DNA was hybridized on the membrane and detected by the chemiluminescence method. We analyzed methylation profile in normal (RWPE1) versus cancerous cells and androgen receptor (AR)-sensitive (LNCaP) versus AR-negative cells (DU145 and PC3). Our study shows that >50% of the genes were hypermethylated in prostate cancer cells compared with 13% in normal cell lines. Among these were the tumor suppressor (RB, TMS1, DAPK, RBL1, PAX6, and FHIT), cell cycle (p27KIP1 and CDKN2A), transporters (MDR1, MLC1, and IGRP), and transcription factor (STAT1, CIITA, MYOD, and NPAT) genes. Relative methylation pattern shows that most of these genes were methylated from 5-fold to >10-fold compared with the normal prostate cells. In addition, promoter methylation was detected for the first time in target genes such as RIOK3, STAT5, CASP8, SRBC, GAGE1, and NPAT. A significant difference in methylation pattern was observed between AR-sensitive versus AR-negative cancer cells for the following genes: CASP8, GPC3, CD14, MGMT, IGRP, MDR1, CDKN2A, GATA3, and IFN. In summary, our study identified candidate genes that are methylated in prostate cancer.

Strimpakos AS, Hoimes C, Saif MW
Pancreatic cancer: translating lessons from mouse models.
JOP. 2009; 10(2):98-103 [PubMed] Related Publications
Pancreatic cancer is the 10th most common cancer and 4th cause of cancer related deaths. Progress in diagnosis and treatment has been slow and disappointing but improvement in understanding of pathogenesis and of molecular changes may offer some ground for rational and etiological approach. During the last ten years the first evidence about the benefit of targeting dysregulated pathways was provided by the study that tried the addition of the EGFR inhibitor erlotinib to the standard cytotoxic gemcitabine. Since then, despite other numerous negative studies, various agents have been investigated in the preclinical and clinical setting and are currently through drug development pipeline. In this year's Gastrointestinal Symposium of the American Society of Clinical Oncology (GI ASCO, San Francisco, 15-17 January 2009), translational and clinical researchers presented evidence of specific genetic variations predicting toxicity (Abstract #115) or efficacy (Abstract #118) of gemcitabine-based treatment and of clinical biomarkers which may serve as predictors of therapy (Abstract #117) or mortality (Abstract #202). We were also informed about the presence of a new surface antigen (CD133) in pancreatic cancer stem cells (Abstract #150) and the development of a recombinant viral vector carrying the G antigen 1 (GAGE1) gene able for B-cells transduction (Abstract #178), which may lead potentially to the development of new immunotherapies and targeted agents. Study and efficacy of novel targeted molecules in preclinical models in vitro and in vivo was also presented (Abstracts #144, 145, 158, 163). In contrast to other malignancies, no mutations of the EGFR/PI3K pathway were found in pancreatic cancer cells not allowing thus a patients' selection approach for EGFR antibodies (Abstract #173).

Jacobs JF, Grauer OM, Brasseur F, et al.
Selective cancer-germline gene expression in pediatric brain tumors.
J Neurooncol. 2008; 88(3):273-80 [PubMed] Free Access to Full Article Related Publications
Cancer-germline genes (CGGs) code for immunogenic antigens that are present in various human tumors and can be targeted by immunotherapy. Their expression has been studied in a wide range of human tumors in adults. We measured the expression of 12 CGGs in pediatric brain tumors, to identify targets for therapeutic cancer vaccines. Real Time PCR was used to quantify the expression of genes MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, MAGE-C2, NY-ESO-1 and GAGE-1,2,8 in 50 pediatric brain tumors of different histological subtypes. Protein expression was examined with immunohistochemistry. Fifty-five percent of the medulloblastomas (n = 11), 86% of the ependymomas (n = 7), 40% of the choroid plexus tumors (n = 5) and 67% of astrocytic tumors (n = 27) expressed one or more CGGs. Immunohistochemical analysis confirmed qPCR results. With exception of a minority of tumors, the overall level of CGG expression in pediatric brain tumors was low. We observed a high expression of at least one CGG in 32% of the samples. CGG-encoded antigens are therefore suitable targets in a very selected group of pediatric patients with a brain tumor. Interestingly, glioblastomas from adult patients expressed CGGs more often and at significantly higher levels compared to pediatric glioblastomas. This observation is in line with the notion that pediatric and adult glioblastomas develop along different genetic pathways.

Jungbluth AA, Silva WA, Iversen K, et al.
Expression of cancer-testis (CT) antigens in placenta.
Cancer Immun. 2007; 7:15 [PubMed] Free Access to Full Article Related Publications
Besides their variable presence in fetal and adult germ cells, CT antigens have occasionally been detected in placental tissue. However, these data are scarce and solely based on mRNA analyses; nothing is known about their presence at the protein level. Here, we analyzed the expression of various CT antigens in placental tissues from gestational age week 5 to week 42 using monoclonal antibodies to various antigens of the MAGE-A and -C families, NY-ESO-1, as well as GAGE. We show that CT antigen expression in placenta varies widely for the various antigens, ranging from completely negative to abundant. Since little is known about the function and biology of CT antigens, interpretation of this highly variable expression pattern is purely speculative. However, our data indicate that the various CT antigens have different functions during placental development.

Condomines M, Hose D, Raynaud P, et al.
Cancer/testis genes in multiple myeloma: expression patterns and prognosis value determined by microarray analysis.
J Immunol. 2007; 178(5):3307-15 [PubMed] Related Publications
Cancer-testis (CT) Ags are expressed in testis and malignant tumors but rarely in nongametogenic tissues. Due to this pattern, they represent attractive targets for cancer vaccination approaches. The aims of the present study are: 1) to assess the expression of CT genes on a pangenomic base in multiple myeloma (MM); 2) to assess the prognosis value of CT gene expression; and 3) to provide selection strategies for CT Ags in clinical vaccination trials. We report the expression pattern of CT genes in purified MM cells (MMC) of 64 patients with newly diagnosed MM and12 patients with monoclonal gammopathy of unknown significance, in normal plasma cell and B cell samples, and in 20 MMC lines. Of the 46 CT genes interrogated by the Affymetrix HG-U133 set arrays, 35 are expressed in the MMC of at least one patient. Of these, 25 are located on chromosome X. The expression of six CT genes is associated with a shorter event-free survival. The MMC of 98% of the patients express at least one CT gene, 86% at least two, and 70% at least three CT genes. By using a set of 10 CT genes including KM-HN-1, MAGE-C1, MAGE-A3/6/12, MAGE-A5, MORC, DDX43, SPACA3, SSX-4, GAGE-1-8, and MAGE-C2, a combination of at least three CT genes-desirable for circumventing tumor escape mechanisms-is obtained in the MMC of 67% of the patients. Provided that the immunogenicity of the products of these 10 CT genes is confirmed, gene expression profiling could be useful in identifying which CT Ags could be used to vaccinate a given patient.

Jacobs JF, Brasseur F, Hulsbergen-van de Kaa CA, et al.
Cancer-germline gene expression in pediatric solid tumors using quantitative real-time PCR.
Int J Cancer. 2007; 120(1):67-74 [PubMed] Related Publications
Cancer-germline genes (CGGs) code for immunogenic antigens that are present on various human tumors but not on normal tissues. The importance of CGGs in cancer immunotherapy has led to detailed studies of their expression in a range of human tumors. We measured the levels of expression of 12 CGGs in various pediatric solid tumors to identify targets for therapeutic cancer vaccines. Quantitative real-time PCR (qPCR) was used to measure the expression of 8 MAGE genes and of genes LAGE-2/NY-ESO-1 and GAGE-1, 2, 8 in 9 osteosarcomas, 10 neuroblastomas, 12 rhabdomyosarcomas and 18 Ewing's sarcomas. Nine tumors were also examined by immunohistochemistry with monoclonal antibodies specific for the MAGE-A1, MAGE-A4 and NY-ESO-1 proteins. All osteosarcoma and 80% of neuroblastoma samples expressed several CGGs at high levels. Six of 12 rhabdomyosarcomas and 11 of 18 Ewing's sarcomas expressed at least one CGG. Immunohistochemistry data correlated well with qPCR results and showed a homogeneous protein distribution pattern in most positive tumors. No correlation was found between the levels of CGG expression in the tumors and clinicopathological parameters of the patients. Pediatric solid tumors express several CGGs, which encode antigens that could be targeted in therapeutic vaccination trials. Several CGGs of the MAGE, GAGE and LAGE families are coexpressed in a large proportion of osteosarcoma and neuroblastoma samples. Some rhabdomyosarcomas express several of these genes at high levels. Ewing's sarcomas have an overall low CGG expression.

Atanackovic D, Blum I, Cao Y, et al.
Expression of cancer-testis antigens as possible targets for antigen-specific immunotherapy in head and neck squamous cell carcinoma.
Cancer Biol Ther. 2006; 5(9):1218-25 [PubMed] Related Publications
Cancer-Testis (CT) antigens are by definition expressed in tumor but not in healthy tissue except testis and might represent ideal targets for antigen-specific immunotherapy. Here, we present the first comprehensive analysis of CT antigen expression in patients with head and neck squamous cell carcinoma (HNSCC). Tumor samples (N = 51), and adjacent healthy tissue from patients with HNSCC were analyzed for the expression of 23 genes designated CT antigens using RT-PCR. Patient sera (N = 39) were screened for IgG antibody responses against NY-ESO-1, MAGEA3, and SSX2. According to their expression pattern antigens were divided into four groups. ADAM2, LIP1, SLLP1, AKAP3, CTAGE, ZNF165, CAGE, and FTHL17 were expressed in tumor and healthy tissue at comparable frequencies. NY-TLU-57, GAGE1, SAGE1 were expressed more frequently in tumor samples than in healthy tissues. TPTE, LDHC, SPO11 were expressed neither in tumor samples nor in healthy tissue. 9 CT antigens were expressed only in the tumor tissue and may represent ideal candidates for active immunotherapy in HNSCC: MAGEA3 was expressed in 72%, SSX1 in 45%, MAGEC2 in 33%, MAGEC1 in 28%, BAGE in 17%, SSX2 in 16%, SCP1 in 12%, NY-ESO-1 in 6%, and HOM-TES-85 in 4% of cases. 86% of tumor samples expressed at least one, 69% expressed at least two, and 43% expressed at least three of these antigens. Three patients showed an antibody response against NY-ESO-1. In conclusion, we demonstrate here that HNSCC frequently express CT antigens. Furthermore, a relatively high percentage of tumors express more than one CT antigen opening the perspective for polyvalent antigen-specific immunotherapy.

Coral S, Sigalotti L, Colizzi F, et al.
Phenotypic and functional changes of human melanoma xenografts induced by DNA hypomethylation: immunotherapeutic implications.
J Cell Physiol. 2006; 207(1):58-66 [PubMed] Related Publications
Emerging in vitro evidence points to an immunomodulatory activity of DNA hypomethylating drugs in human malignancies. We investigated the potential of 5-aza-2'-deoxycytidine (5-AZA-CdR) to modulate the expression of cancer testis antigens (CTA) and of HLA class I antigens by melanoma xenografts, and the resulting modifications in immunogenicity of neoplastic cells. Three primary cultures of melanoma cells, selected for immune phenotype and growth rate, were grafted into BALB/c nu/nu mice that were injected intraperitoneally with different dose- and time-schedules of 5-AZA-CdR. Molecular analyses demonstrated a de novo long-lasting expression of the CTA MAGE-1, -2, -3, -4, -10, GAGE 1-6, NY-ESO-1, and the upregulation of MAGE-1, MAGE-3, and NY-ESO-1 levels in melanoma xenografts from 5-AZA-CdR-treated mice. Serological and biochemical analyses identified a de novo expression of NY-ESO-1 protein and a concomitant and persistent upregulation of HLA class I antigens and of HLA-A1 and -A2 alleles. Immunization of BALB/c mice with 5-AZA-CdR-treated melanoma cells generated high titer circulating anti-NY-ESO-1 antibodies. Altogether, the data obtained identify an immunomodulatory activity of 5-AZA-CdR in vivo and strongly suggest for its clinical use to design novel strategies of CTA-based chemo-immunotherapy for melanoma patients.

Sigalotti L, Fratta E, Coral S, et al.
Intratumor heterogeneity of cancer/testis antigens expression in human cutaneous melanoma is methylation-regulated and functionally reverted by 5-aza-2'-deoxycytidine.
Cancer Res. 2004; 64(24):9167-71 [PubMed] Related Publications
Cancer/testis antigens (CTA) are suitable targets for immunotherapy of human malignancies, and clinical trials are mainly focusing on MAGE-A3. However, the heterogeneous intratumor expression of CTA may hamper the effectiveness of CTA-directed vaccination through the emergence of CTA-negative neoplastic clones. We investigated the intratumor heterogeneity of CTA in human melanoma and the underlying molecular mechanism(s) at clonal level using 14 single cell clones generated from the melanoma lesion Mel 313. Reverse transcription-PCR revealed a highly heterogeneous expression of MAGE-A1, -A2, -A3, -A4, -A6, GAGE 1-6, SSX 1-5, and PRAME among melanoma clones. Only nine clones expressed MAGE-A3 and competitive reverse transcription-PCR identified relative differences in the number of mRNA molecules of up to 130-fold between clones 5 and 14. This clonal heterogeneity of MAGE-A3 expression correlated with the methylation status of specific CpG dinucleotides in MAGE-A3 promoter: i.e., hypomethylated CpG dinucleotides at positions -321, -151, -19, -16, -5, -2, +21, and +42 were found in clones expressing high but not low levels of MAGE-A3. Supporting the role of DNA methylation in generating the intratumor heterogeneity of CTA, the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-dCyd) invariably induced their expression in all CTA-negative clones. Furthermore, 5-AZA-dCyd-treatment reduced to 6 folds the differential expression of MAGE-A3 between clones 5 and 14, which became recognized to a similar extent by T cells specific for a MAGE-A-encoded peptide. These findings identify promoter methylation as directly responsible for the intratumoral heterogeneity of therapeutic CTA in melanoma and foresee the use of 5-AZA-dCyd to overcome the limitations set by their intratumor heterogeneous expression to CTA-based vaccine therapy.

Kong U, Koo J, Choi K, et al.
The expression of GAGE gene can predict aggressive biologic behavior of intestinal type of stomach cancer.
Hepatogastroenterology. 2004 Sep-Oct; 51(59):1519-23 [PubMed] Related Publications
BACKGROUND/AIMS: There is still little information on the function of GAGE gene in stomach cancer except for cancer-specific gene expression recognized by autologous T lymphocytes. This study attempted to detect GAGE expression in stomach cancer to evaluate its clinical implication as a tumor marker or prognosticator as well as to find the candidate for immunotherapy.
METHODOLOGY: Tumor samples from 60 patients and gastric juices from 18 patients with gastric cancer were studied by using RT-PCR with common primer. In-situ RT-PCR and southern blotting were performed to confirm the RT-PCR products.
RESULTS: No expression of GAGE was observed in non-neoplastic juices and tissues. Fifteen out of 60 tumor tissues expressed GAGE (25.0%) mRNA, of which 13 cases (86.7%) were intestinal type and only 2 cases (13.3%) were diffuse type. In gastric juice, 22.2% (4/18) showed mRNA expression, all of which were intestinal type. GAGE expressions in both cancer tissues and gastric juices had a significant tendency to be higher by stage and lymph node metastasis (p<0.05). However, they did not show a significant relationship with tumor cell differentiation and vascular and perineural invasions.
CONCLUSIONS: These results suggest that GAGE gene might have an important role in the development and progression of intestinal type of stomach cancer and the detection of GAGE mRNA may be eligible to the panel of molecular markers for aggressive behavior as well as being useful to a molecule for cancer-specific immunotherapy.

Oltra S, Martínez F, Orellana C, et al.
Minimal residual disease in neuroblastoma: to GAGE or not to GAGE.
Oncol Res. 2004; 14(6):291-5 [PubMed] Related Publications
We assessed the utility of GAGE gene expression as a marker of minimal residual disease (MRD) in neuroblastoma. The GAGE gene family shows a high degree of homology (>90%), clustering into two subgroups. GAGE-1, -2, and -8 form one subset, almost identical among themselves, while GAGE-3 to -7 constitute the other subset. The entire GAGE family (GAGE-1-8) was studied by RT-PCR followed by Southern blotting to increase both the sensitivity and specificity of the technique. Surprisingly, expression of GAGE was detected in 59% of peripheral blood samples from normal controls (20/35) as well as in a similar proportion from neuroblastoma patients with localized disease (stages 1 and 2). The study of GAGE-1, -2, and -8 with specific primers lowered this percentage to 28% (10/35), of which only two (6%) showed a high level of expression (directly visualized after RT-PCR). We conclude that GAGE genes can show a variable, usually low level of illegitimate expression in normal blood cells, and therefore their use as MRD markers should be taken with caution.

Melloni G, Ferreri AJ, Russo V, et al.
Prognostic significance of cancer-testis gene expression in resected non-small cell lung cancer patients.
Oncol Rep. 2004; 12(1):145-51 [PubMed] Related Publications
MAGE, BAGE and GAGE genes encode T cell-defined tumor-associated antigens (TAA), which are expressed by various human tumors and are silent in normal tissues. Because of their expression pattern these TAA have received attention as potential targets for active immunotherapy and as molecular tumor markers. Both of these features are potentially useful in improving treatment of non-small cell lung cancer (NSCLC). We analyzed the expression of some members of the MAGE, BAGE and GAGE gene families by reverse transcription polymerase chain reaction (RT-PCR) in a cohort of 46 NSCLC patients who underwent complete resection and were followed-up for a median period of 41 months. A substantial proportion (range, 25-41%) of NSCLC expressed MAGE-A1, -A2, -A3, GAGE-1, -2, -8 and MAGE-B2 genes. On the contrary, BAGE and MAGE-B1 were expressed less frequently (17% and 11%, respectively). Overall, 59% of NSCLC patients expressed at least one gene and therefore could be eligible for tumor-specific immunotherapy protocols. Moreover, while MAGE-A, BAGE and MAGE-B genes did not provide any prognostic information, GAGE expression was associated with a worse survival (p=0.05). Multivariate analysis confirmed this association, which is independent of TNM stage and other clinicopathologic variables. In conclusion, the detection of GAGE gene expression by RT-PCR appears to be an independent survival predictor in completely resected NSCLC patients.

Gerhardt A, Usener D, Keese M, et al.
Tissue expression and sero-reactivity of tumor-specific antigens in colorectal cancer.
Cancer Lett. 2004; 208(2):197-206 [PubMed] Related Publications
The expression of 14 individual and two groups of tumor antigens was characterized for colorectal carcinoma by RT-PCR using 26 colorectal carcinoma specimens, eight cell lines, six samples of patients with inflammatory bowl diseases, and nine specimens from different locations of an individual patient with a metastasized rectal carcinoma. The most frequently detected mRNAs were MAGE-A1 (58%), GAGE-3-7 (54%), and cTAGE-5a (31%). At medium frequencies (12-19%) we found cTAGE-1, MAGE-A2, se57-1, RAGE-4, and GAGE-1,2,8, while other tumor antigens were expressed rarely (<9%). 85% of the samples were positive for at least one of the most frequently expressed antigens. Using a secondary SEREX approach and sera of eight colorectal cancer patients we found reactive antibodies against recombinant cTAGE-1 (2 sera), se57-1 (2), truncated GAGE (1), and MAGE-A1 (1). We conclude that certain cancer-germline genes can be detected in colorectal cancer and might therefore be promising targets for immunotherapy.

Chen Z, Shao JB, Wu W
Expression of A, G and B melanoma antigen genes in human hepatocellular carcinoma.
Hepatobiliary Pancreat Dis Int. 2002; 1(4):570-3 [PubMed] Related Publications
OBJECTIVE: To observe the expression of the A melanoma antigen (MAGE), G melanoma antigen (GAGE) and B melanoma antigen (BAGE) genes in human hepatocellular carcinoma cell lines.
METHODS: The MAGE-1,MAGE-3,GAGE1-8,GAGE1-2 and BAGE mRNA lever in hepatocellular carcinoma cell lines SMMC-7721, QQY-7701, BEL-7402 were studied by reverse transcription polymerase chain reaction and were compared with biopsied liver tissues.
RESULTS: MAGE-1 and BAGE mRNA were expressed in SMMC-7721, MAGE-3 and BAGE in QGY-7701, MAGE-1 and GAGE1-2 in BEL-7402. None of these genes was expressed in biopsied liver tissues.
CONCLUSIONS: MAGE-1, MAGE-3, GAGE1-8, GAGE1-2 and BAGE were expressed in hepatocellular carcinoma cell lines, respectively. These tumor-specific antigens can be used as molecular markers and possible targets of immunotherapy for patients with hepatocellular carcinoma.

Nagel H, Laskawi R, Eiffert H, Schlott T
Analysis of the tumour suppressor genes, FHIT and WT-1, and the tumour rejection genes, BAGE, GAGE-1/2, HAGE, MAGE-1, and MAGE-3, in benign and malignant neoplasms of the salivary glands.
Mol Pathol. 2003; 56(4):226-31 [PubMed] Free Access to Full Article Related Publications
AIMS: Molecular genetic changes involved in tumorigenesis and malignant transformation of human tumours are novel targets of cancer diagnosis and treatment. This study aimed to analyse the expression of putative tumour suppressor genes, FHIT and WT-1, and tumour rejection genes, BAGE, GAGE-1/2, MAGE-1, MAGE-3, and HAGE (which are reported to be important in human cancers), in salivary gland neoplasms.
METHODS: Gene expression was analysed by reverse transcription polymerase chain reaction (RT-PCR) in normal salivary gland tissue and 44 benign and malignant salivary gland tumours.
RESULTS: Aberrant FHIT transcripts were found in one of 38 normal salivary glands, three of 28 adenomas, and two of 16 carcinomas. WT-1 mRNA was detectable in two adenomas and five carcinomas. Immunoblotting showed that WT-1 mRNA expression was associated with raised WT-1 protein concentrations. RT-PCR for detection of BAGE, GAGE, and MAGE gene expression was positive in two adenomas and nine carcinomas, but negative in normal salivary gland tissue. HAGE mRNA was found in two normal salivary glands, 11 benign, and eight malignant tumours.
CONCLUSIONS: FHIT mRNA splicing does not appear to be involved in the genesis of salivary gland neoplasms. The upregulation of WT-1 mRNA in tumours of epithelial/myoepithelial phenotype may imply a potential role of WT-1 in the genesis and/or cellular differentiation of these salivary gland tumours. The tumour rejection genes were more frequently, but not exclusively, expressed in malignant salivary gland tumours than in benign neoplasms, although none was suitable as a diagnostic marker of malignancy in salivary gland neoplasms.

Sarcevic B, Spagnoli GC, Terracciano L, et al.
Expression of cancer/testis tumor associated antigens in cervical squamous cell carcinoma.
Oncology. 2003; 64(4):443-9 [PubMed] Related Publications
We investigated the expression of tumor-associated antigens (TAA) of the cancer/testis (C/T) gene family in cervical squamous cell carcinomas. First, we focused on the HeLa cervical cancer derived cell line, and we found that it expresses MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A12, GAGE-3/6, LAGE-1, and PRAME genes, encoding defined C/T TAA. In contrast, no expression of MAGE-A10, BAGE, GAGE-1/2, or NY-ESO-1 genes was observed. Corresponding gene products could also be detected by immunoblotting and immunocytochemistry, taking advantage of monoclonal antibodies recognizing discrete TAA. Capitalizing on these data, a monoclonal antibody predominantly recognizing MAGE-A4 TAA in paraffin-embedded sections (57B) was used to investigate the C/T gene expression in clinical tumor samples. A group of 60 patients was studied, and 57B positivity was detectable to different extents in 33% of the cases (20/60). In 13 of them (21%), staining of over 50% of the tumor cells was evident, whereas healthy cells always scored negative. Remarkably, MAGE-A4 expression was significantly (p < 0.05) more frequently detectable in poorly differentiated tumors (8/13) than in well-differentiated or moderately differentiated cancers (3/15 and 9/32, respectively) and in stage FIGO II as compared with stage FIGO Ib tumors (12/23 and 5/24, respectively, p = 0.04). Interestingly, staining was mostly nuclear in well-differentiated tumors, but involved both nuclei and cytoplasm in less differentiated cancers. Positivities of comparable frequency were also detectable in a smaller series of specimens upon staining with MAGE-A1- or NY-ESO-1/LAGE-1-specific reagents. Considering the high tumor specificity of C/T TAA, our data provide the rationale for the design of immunotherapy procedures targeting these antigens in cervical cancers.

Eichmüller S, Usener D, Thiel D, Schadendorf D
Tumor-specific antigens in cutaneous T-cell lymphoma: expression and sero-reactivity.
Int J Cancer. 2003; 104(4):482-7 [PubMed] Related Publications
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of extra-nodal non-Hodgkin lymphomas with primary manifestation in the skin with poor treatment options in the advanced stages. As basis for future immune-therapeutic strategies we have investigated the possible expression of tumor-specific targets in CTCL focusing mainly on so-called cancer-germline genes. cDNAs derived from 20 CTCL tissues and 4 CTCL cell lines were tested with 15 gene-specific and 4 gene family-specific primers by RT-PCR and confirmative Northern blotting. The most frequently detected mRNAs were LAGE-1 (55% with only partial coexpression of the splicing variants), cTAGE-1 (35%), MAGE-A9 (27%) and the GAGE-3-7 group (35%). Furthermore, we could detect NY-ESO-1 (21%) and a MAGE-A subgroup (15%), whereas sub-specification of the latter proved absence of MAGE-A1, -A2, -A3, -A6 and -A12. SCP-1 was found in only one specimen and a several antigens could not been detected in any tumor tissue or cell line (MAGE-B, GAGE-1,2,8 and all 4 RAGE genes). 90% of all CTCL samples were positive for at least 1 of the frequent mRNAs in RT-PCR (LAGE-1, NY-ESO-1, cTAGE-1, MAGE-A9, or GAGE-3to7). Using a secondary SEREX approach we could detect sero-reactivity in sera of CTCL patients against recombinant cTAGE-1 (10/29), GAGE (3/19), MAGE-A1 (1/18), -A3 (1/18), -A6 (2/18) and -A9 (4/18) protein, but not against LAGE-1a, MAGE-A4b or MAGE-A12 protein (n = 19). We conclude, that certain cancer-germline genes can be detected frequently in CTCL and are able to elicit a systemic immune response. These candidate genes might therefore be promising targets for immunotherapeutic interventions in CTCL.

Maio M, Coral S, Sigalotti L, et al.
Analysis of cancer/testis antigens in sporadic medullary thyroid carcinoma: expression and humoral response to NY-ESO-1.
J Clin Endocrinol Metab. 2003; 88(2):748-54 [PubMed] Related Publications
Cancer/testis antigens (CTA) are tumor-associated antigens expressed during ontogenesis, in a number of solid tumors but not in normal tissues except testis. Most of these CTA are highly immunogenic, eliciting a humoral and cellular response in the patients with advanced cancer, and are useful for tumor-specific immunotherapy. Medullary thyroid carcinoma (MTC) is a neoplasm derived from the parafollicular cells of the thyroid and occurs in either a sporadic or a familial form. In the present study, we examined by RT-PCR the expression of a number of genes encoding CTA in 23 surgical samples of sporadic MTC. Among the 11 cDNA antigens examined, RAGE, MAGE-4, and GAGE 1-2, were not expressed in any of the tissues. SSX 2 was present only in one tissue, whereas BAGE, GAGE 1-6, MAGE-1, MAGE-2, MAGE-3, and SSX 1-5 were detected in two to five samples. NY-ESO-1 cDNA was the most frequent, being detected in 15 of 23 examined samples (65.2%). Six (26.1%) tissues did not express any CTA-specific mRNA, whereas 10 tumors expressed only one gene (43.5%), 3 (21.4%) expressed 2 genes, and 4 displayed a broad CTA gene expression. NY-ESO-1 expression in primary MTC tissues significantly correlated with tumor recurrence. The presence of specific anti-NY-ESO-1 antibodies was searched in the sera of MTC-affected patients examined by ELISA using recombinant NY-ESO-1 protein. A humoral response against this CTA was detected in 6 of 11 NY-ESO-1 expressing patients (54.5%), and in 1 of 6 patients with NY-ESO-1-negative tumor. No anti-NY-ESO-1 antibodies were detected in healthy subjects (n = 17). The presence of anti-NY-ESO-1 antibodies was searched also in the sera of MTC affected patients whose tissues were not available for CTA analysis. Anti-NY-ESO-1 antibodies were present in 15 of 42 sera (35.7%), demonstrating that MTC is a neoplasm frequently associated with humoral immune response to NY-ESO-1. Serological survey may be useful as a way to identify patients with humoral immune response to NY-ESO-1 that provide a new attractive target for vaccine-based immunotherapy of MTC.

Götte K, Usener D, Riedel F, et al.
Tumor-associated antigens as possible targets for immune therapy in head and neck cancer: comparative mRNA expression analysis of RAGE and GAGE genes.
Acta Otolaryngol. 2002; 122(5):546-52 [PubMed] Related Publications
Specific immune therapy targeting residual areas of cancer cells may emerge as a powerful treatment strategy for head and neck squamous cell carcinoma (HNSCC). In order to define possible targets for immune therapy, we evaluated the frequency of two groups of tumor antigens-the RAGE and GAGE families-by means of reverse transcriptase polymerase chain reaction using primary HNSCCs (n = 28), mucosa specimens as normal controls (n = 10) and HNSCC cell lines (n = 6). By means of specific primer selection we could differentiate between RAGE-1, -2, -3 and -4, as well as between two groups of GAGE genes (GAGE-1,2,7 vs GAGE-3,4,5,6,8). While all mucosa tissues (from smokers and non-smokers) were negative for both antigen families, 24/28 investigated tumors were positive for up to 5 tumor antigens. Among the RAGE genes, RAGE-1-positive tumors were the most abundant (8/28), followed by RAGE-2 (7/28) and RAGE-4 (6/28). Differences in the locations of HNSCCs were reflected by different RAGE family members being expressed most frequently: larynx, RAGE-1; oropharynx, RAGE-2; and hypopharynx, RAGE-4. Primers against GAGE-1,2,7 and GAGE-3,4,5,6,8 revealed 6/27 and 16/27 positive tumors, respectively. This report suggests that RAGE genes and GAGE-3,4,5,6,8 may be promising candidates for specific immune therapy in HNSCC.

Eichmüller S, Usener D, Jochim A, Schadendorf D
mRNA expression of tumor-associated antigens in melanoma tissues and cell lines.
Exp Dermatol. 2002; 11(4):292-301 [PubMed] Related Publications
Tumor-associated antigens (TAA) are increasingly used as specific targets for immune therapy of malignant melanoma. The aim of the present study was to provide a basis for selecting the most suitable TAA by analyzing the mRNA expression of a large panel of TAA by RT-PCR and Northern blotting. We have chosen primers differentiating four groups of TAA (MAGE-A, MAGE-B, and two groups of GAGE-genes) and 13 individual TAA (MAGE-A2 and -A3, RAGE-1, -2, -3, and -4, LAGE-1a and -1b, NY-ESO-1, GAGE-1, SSX-2, SCP-1, and cTAGE-1) based on most recent sequence data. In addition, the RAGE-gene family has been separated into its four members by a novel designed nested PCR, which was confirmed by Northern analysis. Furthermore, the chromosomal organization and relationship between the RAGE-family and MOK was analyzed. RAGE-4 mRNA could be shown for the first time to be present in testis tissue. The most frequently expressed TAA were the MAGE-A and the GAGE-3,-4,-5,-6,-8 group, whereas among individual TAA MAGE-A2, -A3, RAGE-1, -3, and LAGE-1a/b were found within most specimens and are thus promising candidates for immune therapy. In comparison, melanoma metastatic specimens and cell lines show similar profiles of TAA expression, but individual TAA differ notably between both types of samples indicating that results from cell lines are not always applicable to tumor specimen.

Bert T, Lubomierski N, Gangsauge S, et al.
Expression spectrum and methylation-dependent regulation of melanoma antigen-encoding gene family members in pancreatic cancer cells.
Pancreatology. 2002; 2(2):146-54 [PubMed] Related Publications
Human MAGE and GAGE genes encode tumor-specific antigens presented by HLA I molecules recognized on tumor cells by cytolytic T lymphocytes. To determine if pancreatic cancer patients would be suitable for MAGE- or GAGE-based immunotherapy, the expression frequency of MAGE-A1, -A2, -A3, -A4, -A6 and GAGE1-8 genes was assessed in 15 pancreatic tumor cell lines and 23 pancreatic tumor specimens using reverse transcription-polymerase chain reaction (RT-PCR). In 67% of the cell lines at least one of the MAGE-A genes was detected, 53% revealed concomitant expression of two or more genes. GAGE1-8 expression was detected in 47% of the cell lines. In the primary pancreatic tumors, MAGE-A analysis revealed exclusive MAGE-A1 and MAGE-A2 gene expression in 26 and 30% of the specimens, respectively, independent from clinicopathologic factors. Treatment of MAGE-A expression-negative pancreatic tumor cells with the demethylating agent 5-aza-2'-deoxycytidine could activate MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4 and GAGE transcription suggesting silencing due to promoter methylation. Interestingly, a metastatic lesion to the liver revealed concomittant expression of MAGE-A1, -A2, -A3 and -A6 consistent with a more pronounced genome-wide hypomethylation in metastases. Therefore, a subset of pancreatic cancer patients could be eligible for active, specific immunotherapy directed against MAGE-A antigens and demethylating agents could increase the number of candidate patients.

Hofmann M, Ruschenburg I
mRNA detection of tumor-rejection genes BAGE, GAGE, and MAGE in peritoneal fluid from patients with ovarian carcinoma as a potential diagnostic tool.
Cancer. 2002; 96(3):187-93 [PubMed] Related Publications
BACKGROUND: It has been found that the members of the BAGE, MAGE, and GAGE gene families are expressed almost exclusively in neoplastic tissues. Normal tissues, except testis and placenta, are negative. Therefore, the expression of these genes may serve as a useful diagnostic marker in detecting malignant disease. The involvement of the serous cavities by malignant neoplasms has important therapeutic and prognostic implications. Accordingly, the diagnosis of peritoneal spread of ovarian carcinoma plays an important role for both initial and second-look staging procedures. In some patients, however, a definite diagnosis cannot be established by morphologic or immunocytologic examination alone. Detection of tumor specific gene expression may be a sensitive additional tool in these settings.
METHODS: The authors studied the gene expression observed in 44 ascites specimens. Gene expression was evaluated by reverse transcription-polymerase chain reaction analysis and sequencing.
RESULTS: Of 44 ascites specimens, the expression of BAGE, MAGE-1, MAGE-3, and GAGE-1/2 was recognized in 17 specimens (63%), 2 specimens (7%), 8 specimens (30%), and 8 specimens (30%) with histologically proven ovarian carcinoma, respectively. Expression of the MAGE and GAGE genes was not observed in patients with nonneoplastic disease, whereas BAGE expression was seen in one patient with cirrhosis.
CONCLUSIONS: These findings show that testing for BAGE, GAGE-1/2, MAGE-1, and MAGE-3 transcriptional activity in ascites specimens results in high sensitivity in diagnosing malignant ascites.

Cheung IY, Cheung NK
Detection of microscopic disease: comparing histology, immunocytology, and RT-PCR of tyrosine hydroxylase, GAGE, and MAGE.
Med Pediatr Oncol. 2001; 36(1):210-2 [PubMed] Related Publications
BACKGROUND: We first explored the use of multiple molecular markers to overcome tumor heterogeneity. Sixty-seven neuroblastoma (NB) tumors were tested for the expression of GAGE, MAGE-2, MAGE-2, MAGE-3, and MAGE-4 by RT-PCR and then chemiluminescence; 82% of tumors had detectable GAGE, and 88% expressed at least one of the four MAGE genes.
PROCEDURE AND RESULTS: By combining GAGE and MAGE, 64 of 67 (95%) of tumors became detectable; 17 of 67 coexpressed all five molecular markers. Neither GAGE nor MAGE expression correlated with stage. GAGE was found to have the broadest (18 of 18) expression among stage 4 tumors. Two hundred fifty-nine bone marrows from 99 patients were then studied for NB positivity by four detection methods: histology, immunocytology, and molecular detection by GAGE and tyrosine hydroxylase (TH) mRNA. Two hundred seven samples were NB-positive by one detection method. All four techniques were comparable in detecting tumor cells at diagnosis and at relapse. GAGE and immunocytology were far more sensitive than histology and TH mRNA when marrows were sampled during chemotherapy and at the time of clinical remission.
CONCLUSIONS: By combining multiple molecular markers and independent screening techniques, we may be able to overcome tumor heterogeneity and expedite the detection of microscopic disease in the clinical management of neuroblastoma.

Dalerba P, Frascella E, Macino B, et al.
MAGE, BAGE and GAGE gene expression in human rhabdomyosarcomas.
Int J Cancer. 2001; 93(1):85-90 [PubMed] Related Publications
MAGE, BAGE and GAGE genes encode tumor-associated antigens that are presented by HLA class I molecules and recognized by CD8(+) cytolytic T lymphocytes. These antigens are currently regarded as promising targets for active, specific tumor immunotherapy because MAGE, BAGE and GAGE genes are expressed in many human cancers of different histotype and are silent in normal tissues, with the exception of spermatogonia and placental cells. MAGE, BAGE and GAGE gene expression has been extensively studied in different tumors of adults but is largely unknown in many forms of pediatric solid cancer. Using RT-PCR, we analyzed MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-6, BAGE, GAGE-1,-2 or -8 and GAGE-3,-4,-5,-6 or -7b gene expression in 31 samples of pediatric rhabdomyosarcoma, the most frequent form of malignant soft tissue tumor in children. MAGE genes were expressed in a substantial proportion of patients (MAGE-1, 38%; MAGE-2, 51%; MAGE-3, 35%; MAGE-4, 22%; MAGE-6, 35%), while expression of BAGE (6%); GAGE-1, GAGE-2 and GAGE-8 (9%); and GAGE-3, GAGE-4, GAGE-5, GAGE-6 and GAGE-7B (16%) was less frequent. Overall, 58% of tumors expressed at least 1 gene, and 35% expressed 3 or more genes simultaneously. Our data suggest that a subset of rhabdomyosarcoma patients could be eligible for active, specific immunotherapy directed against MAGE, BAGE and GAGE antigens.

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