BAGE

Gene Summary

Gene:BAGE; B melanoma antigen
Aliases: BAGE1, CT2.1
Location:21p11.1
Summary:This gene encodes a tumor antigen recognized by autologous cytolytic lymphocytes (CTL). [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:B melanoma antigen 1
Source:NCBIAccessed: 13 March, 2017

Ontology:

What does this gene/protein do?
BAGE is implicated in:
- extracellular region
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.

  • Ovarian Cancer
  • Gene Expression
  • T-Lymphocytes, Cytotoxic
  • Organ Specificity
  • Azacitidine
  • Tumor Antigens
  • DEAD-box RNA Helicases
  • ZAP-70 Protein-Tyrosine Kinase
  • Lung Cancer
  • DNA, Complementary
  • Melanoma-Specific Antigens
  • Chromosome 21
  • Hepatocellular Carcinoma
  • Sequence Alignment
  • Antigen Presentation
  • Multiple Myeloma
  • Cancer DNA
  • Statistics, Nonparametric
  • X Chromosome
  • Liver Cancer
  • Molecular Sequence Data
  • Biomarkers, Tumor
  • Cancer Gene Expression Regulation
  • Messenger RNA
  • Transfection
  • Oncogenes
  • DNA Helicases
  • Cloning, Molecular
  • DNA Methylation
  • Breast Cancer
  • Case-Control Studies
  • Amino Acid Sequence
  • Testis
  • Base Sequence
  • Neoplasm Proteins
  • Polymerase Chain Reaction
  • RTPCR
  • Spermatozoa
  • Melanoma
  • Cancer RNA
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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).

Latest Publications: BAGE (cancer-related)

Akiyama Y, Komiyama M, Miyata H, et al.
Novel cancer-testis antigen expression on glioma cell lines derived from high-grade glioma patients.
Oncol Rep. 2014; 31(4):1683-90 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is one of the most malignant and aggressive tumors, and has a very poor prognosis with a mean survival time of <2 years, despite intensive treatment using chemo-radiation. Therefore, novel therapeutic approaches including immunotherapy have been developed against GBM. For the purpose of identifying novel target antigens contributing to GBM treatment, we developed 17 primary glioma cell lines derived from high-grade glioma patients, and analyzed the expression of various tumor antigens and glioma-associated markers using a quantitative PCR and immunohistochemistry (IHC). A quantitative PCR using 54 cancer-testis (CT) antigen-specific primers showed that 36 CT antigens were positive in at least 1 of 17 serum-derived cell lines, and 17 antigens were positive in >50% cell lines. Impressively, 6 genes (BAGE, MAGE-A12, CASC5, CTAGE1, DDX43 and IL-13RA2) were detected in all cell lines. The expression of other 13 glioma-associated antigens than CT genes were also investigated, and 10 genes were detected in >70% cell lines. The expression of CT antigen and glioma-associated antigen genes with a high frequency were also verified in IHC analysis. Moreover, a relationship of antigen gene expressions with a high frequency to overall survival was investigated using the Repository of Molecular Brain Neoplasia Data (REMBRANDT) database of the National Cancer Institute, and expression of 6 genes including IL-13RA2 was inversely correlated to overall survival time. Furthermore, 4 genes including DDX43, TDRD1, HER2 and gp100 were identified as MGMT-relevant factors. In the present study, several CT antigen including novel genes were detected in high-grade glioma primary cell lines, which might contribute to developing novel immunotherapy and glioma-specific biomarkers in future.

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.

Syed ON, Mandigo CE, Killory BD, et al.
Cancer-testis and melanocyte-differentiation antigen expression in malignant glioma and meningioma.
J Clin Neurosci. 2012; 19(7):1016-21 [PubMed] Related Publications
Identification of well-defined glioma-specific antigens is a crucial and necessary step in developing immunotherapy for glioblastoma multiforme (GBM). In this study, we analyzed the composite expression of cancer-testis antigens (CTA) and melanocyte-differentiation antigens (MDA) in malignant glioma tissue and primary glioma cell lines and compared them with normal brain specimens and meningioma. CTA and MDA expression was assessed by the reverse transcription-polymerase chain reaction. The following primers were analyzed for CTA: LAGE-1, NY-ESO-1, MAGE-1, MAGE-3, MAGE-4, MAGE-10, CT-7, CT-10, HOM-MEL 40, BAGE, and SCP-1; and for MDA: tyrosinase, gp100, MELAN-A/MART-1, and TRP-2. The expression level was determined by ethidium bromide-stained agarose gel. Among malignant glioma tissue, the highest CTA and MDA expression rates were found for MAGE-3 (22%), MAGE-1 (16%), CT-7 (11%), gp100 (40%), and TRP-2 (29%). Among primary glioma cell lines, the highest levels of expression were: CT-10 (38%), gp100 (100%), and TRP-2 (31%). NY-ESO-1 was the only CTA demonstrated and seen in 12% of meningioma tissue specimens. TRP-2 and gp100 were expressed in 65% and 38% of meningioma tissue, respectively; gp100 and TRP-2 were expressed in 100% and 50% of meningioma cell lines. Of the nine normal brain specimens, all samples tested positive for TRP-2. All other CTA and MDA tested negative in normal brain. We conclude that CTA and MDA demonstrate low-to-variable levels of expression within GBM. However, two CTA (MAGE-1 and MAGE-3) and one MDA (gp100) may be considered candidate antigens based on their restricted expression in GBM. These results will greatly accelerate the development of novel, specific immunotherapeutic strategies.

Guediche N, Tosca L, Kara Terki A, et al.
Array comparative genomic hybridization analysis of small supernumerary marker chromosomes in human infertility.
Reprod Biomed Online. 2012; 24(1):72-82 [PubMed] Related Publications
Small supernumerary marker chromosomes (sSMC) are structurally abnormal chromosomes that cannot be unambiguously identified by conventional banding cytogenetics. This study describes four patients with sSMC in relation with infertility. Patient 1 had primary infertility. His brother, fertile, carried the same sSMC (patient 2). Patient 3 presented polycystic ovary syndrome and patient 4 primary ovarian insufficiency. Cytogenetic studies, array comparative genomic hybridization (CGH) and sperm analyses were compared with cases previously reported. sSMC corresponded to the 15q11.2 region (patients 1 and 2), the centromeric chromosome 15 region (patient 3) and the 21p11.2 region (patient 4). Array CGH showed 3.6-Mb gain for patients 1 and 2 and 0.266-Mb gain for patient 4. Sperm fluorescent in-situ hybridization analyses found ratios of 0.37 and 0.30 of sperm nuclei with sSMC(15) for patients 1 and 2, respectively (P < 0.001). An increase of sperm nuclei with disomy X, Y and 18 was noted for patient 1 compared with control and patient 2 (P < 0.001). Among the genes mapped in the unbalanced chromosomal regions, POTE B and BAGE are related to the testis and ovary, respectively. The implication of sSMC in infertility could be due to duplication, but also to mechanical effects perturbing meiosis.

Yuan Y, Curtis C, Caldas C, Markowetz F
A sparse regulatory network of copy-number driven gene expression reveals putative breast cancer oncogenes.
IEEE/ACM Trans Comput Biol Bioinform. 2012 Jul-Aug; 9(4):947-54 [PubMed] Related Publications
UNLABELLED: Copy number aberrations are recognized to be important in cancer as they may localize to regions harboring oncogenes or tumor suppressors. Such genomic alterations mediate phenotypic changes through their impact on expression. Both cis- and transacting alterations are important since they may help to elucidate putative cancer genes. However, amidst numerous passenger genes, trans-effects are less well studied due to the computational difficulty in detecting weak and sparse signals in the data, and yet may influence multiple genes on a global scale. We propose an integrative approach to learn a sparse interaction network of DNA copy-number regions with their downstream transcriptional targets in breast cancer. With respect to goodness of fit on both simulated and real data, the performance of sparse network inference is no worse than other state-of-the-art models but with the advantage of simultaneous feature selection and efficiency. The DNA-RNA interaction network helps to distinguish copy-number driven expression alterations from those that are copy-number independent. Further, our approach yields a quantitative copy-number dependency score, which distinguishes cis- versus trans-effects. When applied to a breast cancer data set, numerous expression profiles were impacted by cis-acting copy-number alterations, including several known oncogenes such as GRB7, ERBB2, and LSM1. Several trans-acting alterations were also identified, impacting genes such as ADAM2 and BAGE, which warrant further investigation.
AVAILABILITY: An R package named lol is available from www.markowetzlab.org/software/lol.html.

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.

Grunau C, Brun ME, Rivals I, et al.
BAGE hypomethylation, a new epigenetic biomarker for colon cancer detection.
Cancer Epidemiol Biomarkers Prev. 2008; 17(6):1374-9 [PubMed] Related Publications
Early detection of colorectal cancer is a decisive step in the successful and complete cure of the disease. Epigenetic markers, in particular, those based on aberrant DNA methylation, can be used to diagnose cancer. B melanoma antigens (BAGE) are a family of genes and truncated genes located in the heterochromatic regions of several human chromosomes. Our previous work showed that BAGE loci (i.e., genes and truncated genes) were hypermethylated in normal tissues and hypomethylated in 98% of human cancers. In the present study, we analyzed DNA methylation of the BAGE loci in 54 colon cancers and in neighboring histopathologic normal tissue samples. Using a combined bisulfite restriction assay, we showed that BAGE loci were hypomethylated in 81% of carcinoma samples. Colon cancer could be diagnosed with 94% specificity, 83% sensitivity, and 89% accuracy. No correlation was found between DNA methylation of BAGE loci and age, gender of patients, nor with the tumor stage or site. Based on the hypothesis that during neoplastic transformation, hypomethylation occurs in juxtacentromeric CpG islands, we suggest that other genes located in the heterochromatic compartment should be tested. These new markers enrich the list of currently studied epigenetic alterations in colon cancer and could be associated with hypermethylation markers to develop reliable diagnostic tests.

Seifert A, Klonisch T, Wulfaenger J, et al.
The cellular localization of autotaxin impacts on its biological functions in human thyroid carcinoma cells.
Oncol Rep. 2008; 19(6):1485-91 [PubMed] Related Publications
Autotaxin (ATX/NPP2) shows a nucleotide pyrophosphatase/phosphodiesterase and lysophospholipase D (lysoPLD) activity and is a member of a family of structurally-related mammalian ecto-nucleotide pyrophosphate/phosphodiesterases (E-NPP1-3). ATX is unique among E-NPP as it is secreted and not membrane-bound as are NPP1 and -3. The ATX gene activity is significantly higher in undifferentiated anaplastic (UTC) as compared to follicular (FTC) and papillary thyroid carcinomas (PTC) or goiter tissues. ATX also enhances the motility of thyroid tumor cells. We bio-engineered stable transfectants of the human thyroid carcinoma cell line FTC-238 expressing either bioactively-secreted (sATX) or membrane-anchored ATX (mATX) to identify the biological functions of ATX which critically depend on the E-NPP member being secreted and provide insight into the effects of high local ATX concentrations and cellular responses. An increased cell motility was exclusively observed with FTC-238 sATX transfectants, whereas membrane-anchored ATX appeared to impair motility. We identified IL-1beta as an upstream suppressor of ATX expression in FTC-238, ATX-mediated motility in FTC-238 and stable transfectants, with IL-1beta having the strongest motility-suppressive effect on FTC-238 sATX clones. sATX and mATX strongly increased the anchorage-independent colony formation of FTC-238 but the size and number of colonies formed in the soft agar were significantly smaller in FTC-238 mATX versus the FTC-238 sATX clones. The cancer-testis antigen BAGE was identified as a novel target gene of ATX in FTC-238. Transcript levels for BAGE were 6-fold higher in FTC-238 mATX versus sATX clones. Increased BAGE transcript levels were also detected in tissues of patients with UTC versus FTC, PTC or goiter tissues. In summary, enhanced tumor cell motility and tumorigenic capacity critically depended on sATX in thyroid carcinoma cells. Irrespective of its compartmentalization, the cancer-testis antigen BAGE was identified as a novel target gene of ATX in FTC-238 and a potential new tissue marker in UTC tissues, which we had previously shown to express high levels of ATX.

Andrade VC, Vettore AL, Felix RS, et al.
Prognostic impact of cancer/testis antigen expression in advanced stage multiple myeloma patients.
Cancer Immun. 2008; 8:2 [PubMed] Free Access to Full Article Related Publications
This study aims to analyze the expression of 14 cancer/testis (CT) antigens in multiple myeloma (MM) to identify possible prognostic markers and therapeutic targets. The expression of MAGEA1, MAGEA2, MAGEA3/6, MAGEA4, MAGEA10, MAGEA12, BAGE1, MAGEC1/CT7, the GAGE family, LAGE-1, PRAME, NY-ESO-1, SPA17 and SSX1 was studied by RT-PCR in 15 normal tissues, a pool of 10 normal bone marrow samples, 3 normal tonsils and bone marrow aspirates from 6 normal donors, 3 monoclonal gammopathies of undetermined significance (MGUS), 5 solitary plasmacytomas, 39 MM samples (95% advanced stage) and the MM cell line U266. MAGEC1/CT7 was expressed in bone marrow aspirates from one MGUS and one plasmacytoma. The frequencies at which CT antigen were found to be expressed in MM patients were MAGEC1/CT7 77%, LAGE-1 49%, MAGEA3/6 41%, MAGEA2 36%, GAGE family 33%, NY-ESO-1 33%, BAGE-1 28%, MAGEA1 26%, PRAME 23%, SSX-1 26%, MAGEA12 20.5%, MAGEA4 0%, and MAGEA10 0%. Cox's regression model showed that GAGE family expression and having >6 CT antigens expressed were independent prognostic factors when all patients were analyzed. However, MAGEC1/CT7 expression was the only independent prognostic factor when non-transplanted patients where analyzed. Based on our findings, MAGEC1/CT7, MAGEA3/6 and LAGE-1 are good candidates for immunotherapy, since together they cover 85% of our MM cases. Furthermore, expression of the GAGE family, >6 CT antigens and MAGEC1/CT7 seem to have impact on MM prognosis.

Atanackovic D, Arfsten J, Cao Y, et al.
Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation.
Blood. 2007; 109(3):1103-12 [PubMed] Related Publications
Immunotherapies using cancer-testis (CT) antigens as targets represent a potentially useful treatment in patients with multiple myeloma (MM) who commonly show recurrent disease following chemotherapy. We analyzed the expression of 11 CT antigens in bone marrow samples from patients with MM (n=55) and healthy donors (n=32) using reverse transcriptase-polymerase chain reaction (RT-PCR). CT antigens were frequently expressed in MM with 56% (MAGEC2), 55% (MAGEA3), 35% (SSX1), 20% (SSX4, SSX5), 16% (SSX2), 15% (BAGE), 7% (NY-ESO-1), and 6% (ADAM2, LIPI) expressing the given antigen. Importantly, CT antigens were not expressed in healthy bone marrow. Analyzing patients with MM (n=66) for antibody responses against MAGEA3, SSX2, and NY-ESO-1, we found strong antibody responses against CT antigens preferentially in patients who had received allogeneic stem cell transplantation (alloSCT). Antibody responses against NY-ESO-1 correlated with NY-ESO-1-specific CD4+ and CD8+ T-cell responses against peptide NY-ESO-1(51-62) and CD4+ responses against NY-ESO-1(121-140) in 1 of these patients. These allogeneic immune responses were not detectable in pretransplantation samples and in the patients' stem cell donors, indicating that CT antigens might indeed represent natural targets for graft-versus-myeloma effects. Immune responses induced by alloSCT could be boosted by active CT antigen-specific immunotherapy, which might help to achieve long-lasting remissions in patients with MM.

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.

Giannopoulos K, Li L, Bojarska-Junak A, et al.
Expression of RHAMM/CD168 and other tumor-associated antigens in patients with B-cell chronic lymphocytic leukemia.
Int J Oncol. 2006; 29(1):95-103 [PubMed] Related Publications
Antigen targeted immunotherapies might represent a novel treatment for B-cell chronic lymphocytic leukemia (B-CLL). We screened the mRNA expression of tumor-associated antigens (TAAs) from the literature (fibromodulin, survivin, OFA-iLRP, BAGE, G250, MAGE1, PRAME, proteinase, syntaxin, hTERT, WT-1) and TAAs defined previously by serological analysis of cDNA expression libraries from leukemic cells (PINCH, HSJ2, MAZ, MPP11, RHAMM/CD168, NY-Ren60). Peripheral blood mononuclear cells from 43 B-CLL patients and 20 healthy volunteers (HVs) were examined by conventional and quantitative RT-PCR. mRNA of RHAMM/CD168, fibromodulin, syntaxin and NY-Ren60 was expressed in 55-90%, and mRNA of HSJ2, MAZ and OFAiLRP was expressed in 90-100% of the patients. No expression of WT-1, hTERT, BAGE, G250, MAGE1 or survivin was observed. Low (2-20%) expression frequencies of MPP11, PINCH, PRAME and proteinase were detected. RHAMM/CD168, fibromodulin, PRAME and MPP11 showed expression in B-CLL patients, but not in HVs. Because of the exquisite tissue expression of RHAMM/CD168 and its high expression frequency in CLL patients, mixed lymphocyte peptide culture (MLPC), enzyme-linked immunosorbent spot (ELISPOT) and flow cytometry were performed for antigen specific T-cells. In MLPC, RHAMM specific responses by CD8+HLA-A2/R3tetramer+CCR7-CD45RAhigh effector T-cells were detected. RHAMM/CD168 might be a possible target for future immunotherapies in both ZAP-70(+) and ZAP-70(-) B-CLL patients.

Fradet Y, Picard V, Bergeron A, LaRue H
Cancer-testis antigen expression in bladder cancer.
Prog Urol. 2005; 15(6 Suppl 1):1303-13 [PubMed] Related Publications
PURPOSE: To evaluate the potential of cCancer-t/Testis antigens (CTAs) as targets for immunotherapy of bladder cancer, we evaluated the expression of 9 CTA genes or families of genes in normal urothelia, bladder tumours and bladder cancer human bladder tissuescell lines. As expression of most CTAs is controlled by epigenetic mechanisms, we also evaluated the effect of the DNA methylase inhibitor 5-aza-2'-deoxycytidine (5-AZA-DC), and/or theand histone deacetylase inhibitors Trichostatin A (TSA) on their expression in bladder cancer cell lines.
MATERIAL AND METHODS: Expression of NY-ESO-1/LAGE-1, MAGE-A, MAGE-C1, BAGE, HOM-TES-85, SCP-1, SSX-1, SSX-2 and SSX-4 was analyzed by semi-quantitative RT-PCR and Western blotting on 10 normal urothelia, 23 24 superficial and 223 invasive tumours and on 10 cell lines treated with 5-aza-2'-deoxycytidine (5-AZA-DC) and/or Trichostatin A (TSA).
RESULTS: Expression of all CTA genes could be observed in at least 1 tumour except for HOM-TES-85 for which mRNA was never detected. MAGE-A, BAGE and NY-ESO-1/LAGE-1 mRNAs were the most frequently detected, respectively in 5677%, 212% and 89% of superficial and in 6461%, 4139% and 276% of invasive tumours. With the exception of MAGE-A, CTA transcripts were rarely detected in the cell lines. However, expression of all CTA genes, except SCP-1, could be induced at various levels by the drugs and 5-AZA-DC was a much more potent inducer than TSA.
CONCLUSION: These data suggest that immunotherapy of bladder cancer could target CTAs, especially those expressed at higher frequency such as MAGE-A, BAGE and NY-ESO-1/LAGE-1. Moreover, their induction by chemotherapeutic agents such as 5-AZA-DC, provides a potential pretreatment aimed at inducing the immunogenicity of the tumours.

Grunau C, Sanchez C, Ehrlich M, et al.
Frequent DNA hypomethylation of human juxtacentromeric BAGE loci in cancer.
Genes Chromosomes Cancer. 2005; 43(1):11-24 [PubMed] Related Publications
The BAGE (B melanoma antigens) sequence family contains 15 nearly identical sequences that are in the juxtacentromeric regions of chromosomes 9, 13, 18, and 21. BAGE loci are expressed in male germ tissue and in a high percentage of cancers and cancer cell lines. We analyzed the DNA methylation state of the sequences in or near the promoters of the BAGE loci by a quantitative bisulfite and PCR-based assay (multiplex COBRA) using MboI and HphI in 18 somatic tissue samples, 4 testis and 4 sperm samples, and 48 tumors and tumor cell lines. In 94% of the control somatic tissue samples, DNA was highly methylated in the analyzed regions. In contrast, 98% of tumor DNA samples displayed hypomethylation. Also, DNA from testes and sperm was hypomethylated in at least one of the BAGE loci. BAGE transcripts were observed in only 47% of the analyzed tumor samples. Consequently, we propose BAGE hypomethylation as a new, highly informative epigenetic biomarker for the diagnosis of cancer, whose hypomethylation in cancer may be causally related to that of juxtacentromeric satellite DNA.

Segal NH, Blachere NE, Guevara-Patiño JA, et al.
Identification of cancer-testis genes expressed by melanoma and soft tissue sarcoma using bioinformatics.
Cancer Immun. 2005; 5:2 [PubMed] Related Publications
Cancer-testis or germ cell antigens (GCAs) are a category of tumor antigens expressed by male germ cells and by cancers of diverse histological origin, but not usually by normal adult somatic tissue. These antigens include products encoded by the MAGE, BAGE, GAGE, SSX, and LAGE/NY-ESO-1 families that encode antigenic peptides recognized by T lymphocytes. In this study, we exploit oligonucleotide technology to identify genes in melanoma and soft tissue sarcoma (STS) that display a cancer-testis/GCA expression profile. We identified 59 such genes, including GCAs we knew to be recognized by T lymphocytes. Among our findings are the expression of PRAME in monophasic synovial sarcoma, PRAME and NY-ESO-1 in myxoid/round cell liposarcoma, and SSX2 and members of the GAGE family in malignant fibrous histiocytoma. Furthermore, the proto-oncogene DBL/MCF2 was identified as encoding a novel candidate GCA expressed by clear cell sarcoma/melanoma of soft parts (MSP). DBL/MCF2 peptides that are bound to HLA-A*0201 were identified and recognized by T lymphocytes. These results show the utility of high-throughput expression analysis in the efficient screening and identification of GCA candidates in cancer, and its application to the discovery of candidate targets for T cell immunity against GCAs expressed by cancer.

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.

Greiner J, Ringhoffer M, Taniguchi M, et al.
mRNA expression of leukemia-associated antigens in patients with acute myeloid leukemia for the development of specific immunotherapies.
Int J Cancer. 2004; 108(5):704-11 [PubMed] Related Publications
Specific immunotherapies for patients with acute myeloid leukemia (AML) using leukemia-associated antigens (LAA) as target structures might be a therapeutic option to enhance the graft-vs.-leukemia effect observed after allogeneic stem cell transplantation or to prolong a complete remission (CR) achieved by chemotherapy. Significant mRNA expression of LAA is a prerequisite for such immunotherapies. Here, previously characterized antigens associated with solid tumors (TAA) and newly characterized LAA were investigated for their expression in up to 60 AML patients and in leukemia cell lines. To investigate their specificity for leukemic blasts, the mRNA expression was also characterized in PBMN and CD34 positive cells of healthy volunteers and in a panel of normal tissues. The following antigens showed high mRNA expression in AML patients: MPP11 was detected in 43/50 (86%), RHAMM in 35/50 (70%), WT1 in 40/60 (67%), PRAME in 32/50 (64%), G250 in 18/35 (51%), hTERT in 7/25 (28%) and BAGE in 8/30 (27%) of AML patients. Real-time RT-PCR showed a tumor-specific expression of the antigens BAGE, G250 and hTERT, as well as highly tumor-restricted expression for RHAMM, PRAME and WT1. The antigen MPP11 was overexpressed. These antigens might be candidates for immunotherapies of leukemia patients and, because of their simultaneous expression, also for polyvalent vaccines.

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.

Tajima K, Obata Y, Tamaki H, et al.
Expression of cancer/testis (CT) antigens in lung cancer.
Lung Cancer. 2003; 42(1):23-33 [PubMed] Related Publications
Cancer/testis (CT) antigens are considered promising candidates for vaccine-based immunotherapy. The aim of this study was to investigate which CT antigens should be targeted in immunotherapy of Japanese lung cancer. To determine the expression of 12 CT antigens in Japanese primary lung cancers and cell lines, a reverse-transcription polymerase chain reaction (RT-PCR) analysis was performed. Among 46 primary lung cancers, high expression rates were found for MAGE-3 (41%, 19/46), and SSX-4 (35%, 16/46). A similar pattern of CT antigen expression was observed in 29 lung cancer cell lines. The expression frequency of a certain CT antigen, namely NY-ESO-1, in Japanese cases was drastically different from that in Caucasians. Polyvalent CT antigen vaccine may be effective to increase the number of lung cancer patients eligible for cancer-specific immunotherapy. Vaccination with MAGE-3 and SSX-1 would cover 57% of all patients, with three antigens, MAGE-3, SSX-1, and MAGE-4, would cover 65%, and with four antigens, MAGE-3, SSX-1, MAGE-4 and SSX-4, would cover 70%. Simultaneous expression of two or more CT antigens was observed in 25/46 (54%) primary lung cancers and 18/29 (62%) lung cancer cell lines. Polyvalent CT antigen vaccines may be also effective to reduce a chance of emergence of antigen loss variants, thus preventing tumors from escaping from the immune system. For this purpose, vaccination with combinations of MAGE-3 with MAGE-6, SSX-4, MAGE-1 or BAGE may be effective for a quarter of Japanese lung cancer patients. In addition, in silico surveys of dbEST database were used for identification of new CT antigens. We identified a novel gene, TES101RP, expressed only in some small cell lung cancers (SCLC) and in testis, as confirmed by RT-PCR analysis.

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.

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.

Ruault M, van der Bruggen P, Brun ME, et al.
New BAGE (B melanoma antigen) genes mapping to the juxtacentromeric regions of human chromosomes 13 and 21 have a cancer/testis expression profile.
Eur J Hum Genet. 2002; 10(12):833-40 [PubMed] Related Publications
A first BAGE (B melanoma antigen) gene, BAGE1, was identified because it encodes a human tumour antigen recognised by a cytolytic T lymphocyte. Here, we characterised five new BAGE genes mapping to the juxtacentromeric regions of human chromosomes 13 and 21 and nine BAGE gene fragments mapping to the juxtacentromeric regions of chromosomes 9, 13, 18, and 21. Genes and gene fragments share extensive regions of 90-99% nucleotide identity. We analysed the expression of BAGE genes on 215 tumours of various histological types and on nine normal tissues. Similar to BAGE1, the new BAGE genes are expressed in melanomas, bladder and lung carcinomas and in a few tumours of other histological types. All the normal tissues were negative, with the exception of testis. Our results show that human juxtacentromeric regions harbour genes, which are transcribed and translated, in addition to gene fragments that are generally not expressed. We suggest that the pattern of expression restricted to cancer/testis is a feature of the few genes mapping to juxtacentromeric regions.

Adams SP, Sahota SS, Mijovic A, et al.
Frequent expression of HAGE in presentation chronic myeloid leukaemias.
Leukemia. 2002; 16(11):2238-42 [PubMed] Related Publications
Cancer testis (CT) antigens provide attractive targets for cancer-specific immunotherapy. Although CT genes are expressed in some normal tissues, such as the testis and in some cases placenta, these immunologically protected sites lack MHC I expression and as such, do not present 'self' antigens to T cells. To date, CT genes have been shown to be expressed in a range of solid tumours, but rarely in haematological malignancies. We have extended previous studies to investigate the expression of a comprehensive range of CT genes (MAGE-A1, -A3, -A6, -A12, BAGE, GAGE, HAGE,LAGE-1, NY-ESO-1 and RAGE) for their expression in a cohort of acute and chronic myeloid leukaemia patient samples. CT expression was not detected in 20 normal bone marrow or peripheral blood stem cell samples. In acute myeloid leukaemia (AML) nine of the 26 (35%) samples analysed expressed one or more of the CT genes with six of the samples (23%) expressing HAGE. In chronic myeloid leukaemia (CML) 24 of 42 (57%) presentation chronic myeloid leukaemia (CML) patient samples expressed one or more CT antigen with 23 expressing HAGE. We have shown that HAGE is frequently expressed in CML, and to a lesser extent in AML patient samples. This is the first demonstration of HAGE gene expression in myeloid leukaemia patients and the frequent expression of HAGE at disease presentation opens up the possibility of early immunotherapeutic treatments.

Bodey B
Cancer-testis antigens: promising targets for antigen directed antineoplastic immunotherapy.
Expert Opin Biol Ther. 2002; 2(6):577-84 [PubMed] Related Publications
During the last decade, the aberrant expression of normal testicular proteins in neoplastically transformed cells became common knowledge. Cancer-testis antigens (CTAs) represent a novel family of immunogenic proteins. The genes MAGE, BAGE, GAGE, LAGE and NY-ESO-1 code for antigens that are recognised on various neoplastically transformed cells by autologous, cytolytic CD8 ( + ) T lymphocytes. The MAGE genes were initially analysed from melanomas and turned out to have an almost exclusively neoplasm specific expression pattern. In normal adult tissues, most 23 human MAGE genes are expressed only in the testis, with expression patterns suggesting that this gene family is involved in germ cell development. The SSX (synovial sarcoma on X chromosome) gene family, located on the X chromosome, encode a family of highly homologous nuclear proteins. A number of observations confirmed that all five SSX genes were expressed in normal testis. The newly detected CTA, NY-ESO-1, is regarded as one of the most immunogenic antigens ever isolated, inducing spontaneous host immune responses in 50% of patients with NY-ESO-1-expressing neoplasms. The identification of neoplasm-associated markers recognised by cellular or humoral effectors of the immune system has opened new perspectives for antigen directed, individualised antineoplastic immunotherapy. In preparation for this new era of targeted immunotherapy, a number of neoplasm-associated antigen families have been identified as targets for CD8+, cytolytic T lymphocytes in vitro and in vivo : (1) CTAs expressed in various neoplasms and in normal testis, restricted to male germ cells; (2) melanocyte differentiation antigens; (3) point mutations of normal genes; (4) antigens overexpressed in neoplastic tissues; and (5) viral antigens. Immunotherapeutic protocols directed against the CTAs have already been initiated to analyse the induction of antigen-specific cellular and humoral immune responses in vivo.

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.

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.

Zambon A, Mandruzzato S, Parenti A, et al.
MAGE, BAGE, and GAGE gene expression in patients with esophageal squamous cell carcinoma and adenocarcinoma of the gastric cardia.
Cancer. 2001; 91(10):1882-8 [PubMed] Related Publications
BACKGROUND: The MAGE, BAGE, and GAGE gene families code for distinct, tumor specific antigens that are recognized by cytotoxic T lymphocytes in the context of HLA molecules. The purpose of this study was to analyze MAGE, BAGE, and GAGE gene expression in the two major histologic types of esophageal carcinoma, squamous carcinoma (ESCc) and adenocarcinoma (CAc), and to correlate their expression patterns with the principal prognostic parameters and long term survival.
METHODS: Gene expression was analyzed in surgical samples from 24 patients with ESCc and 24 patients with CAc by reverse transcriptase-polymerase chain reaction amplification (RT-PCR). None of the patients had received preoperative chemotherapy or radiotherapy, and all were followed until death or for a minimum of 4 years.
RESULTS: Sixteen ESCc samples (67%) and 9 CAc samples (37.5%) expressed at least one of the genes under study. The expression of each MAGE gene in the two histologic types was not significantly different, with the exception of MAGE-4, which was expressed more in ESCc samples than in CAc samples. BAGE and GAGE expression was rather low and, in every case, was associated with the expression of at least one MAGE gene.
CONCLUSIONS: In the group as a whole, and in both ESCc and CAc subgroups, no significant correlation emerged between the expression of any gene and prognostic parameters, such as pathologic tumor, lymph node, or disease stage. Nevertheless, BAGE or GAGE expression was related significantly to a poor prognosis, whereas the expression of MAGE genes (in the absence of BAGE and GAGE expression) was related significantly to a good prognosis.

Abu-Shakra M, Buskila D, Ehrenfeld M, et al.
Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies.
Ann Rheum Dis. 2001; 60(5):433-41 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To review the autoimmune and rheumatic manifestations of patients with malignancy.
METHODS: A Medline search of all published papers using keywords related to malignancies, autoimmunity, rheumatic diseases, and paraneoplastic syndromes.
RESULTS: Patients with malignant diseases may develop autoimmune phenomena and rheumatic diseases as a result of (a) generation of autoantibodies against various autoantigens, including oncoproteins (P185, 1-myc, c-myc, c-myb), tumour suppression genes (P53), proliferation associated antigens (cyclin A, B1, D1, E; CENP-F; CDK, U3-RNP), onconeural antigens (Hu, Yo, Ri, Tr), cancer/testis antigens (MAGE, GAGE, BAGE, SSX, ESO, SCP, CT7), and rheumatic disease associated antigens (RNP, Sm). The clinical significance of the various autoantibodies is not clear. Anti-oncoprotein and anti-tumour suppression gene antigens are detected before the diagnosis of the cancer or in the early stages of the malignant disease, suggesting a potential diagnostic or prognostic role. Anti-onconeural antibodies are pathogenic and are associated with specific clinical neurological syndromes (anti-Hu syndrome and others). (b) Paraneoplastic syndromes, a wide range of clinical syndromes, including classic autoimmune rheumatic diseases that develop among patients with cancer. (c) Rheumatism after chemotherapy, a clinical entity characterised by the development of musculoskeletal symptoms after combination chemotherapy for malignancy.
CONCLUSION: Autoimmune and rheumatic features are not rare among patients with malignancies. They are the result of various diverse mechanisms and occasionally they may be associated with serious clinical entities.

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