Characterization of the GAGE genes that are expressed in various human cancers and in normal testis.
The GAGE-1 gene was identified previously as a gene that codes for an antigenic peptide, YRPRPRRY, which was presented on a human melanoma by HLA-Cw6 molecules and recognized by a clone of CTLs derived from the patient bearing the tumor. By screening a cDNA library from this melanoma, we identified five additional, closely related genes named GAGE-2-6. We report here that further screening of this library led to the identification of two more genes, GAGE-7B and -8. GAGE-1, -2, and -8 code for peptide YRPRPRRY. Using another antitumor CTL clone isolated from the same melanoma patient, we identified antigenic peptide, YYWPRPRRY, which is encoded by GAGE-3, -4, -5, -6, and -7B and which is presented by HLA-A29 molecules. Genomic cloning of GAGE-7B showed that it is composed of five exons. Sequence alignment showed that an additional exon, which is present only in the mRNA of GAGE-1, has been disrupted in gene GAGE-7B by the insertion of a long interspersed repeated element retroposon. These GAGE genes are located in the p11.2-p11.4 region of chromosome X. They are not expressed in normal tissues, except in testis, but a large proportion of tumors of various histological origins express at least one of these genes. Treatment of normal and tumor cultured cells with a demethylating agent, azadeoxycytidine, resulted in the transcriptional activation of GAGE genes, suggesting that their expression in tumors results from a demethylation process.
Ludwig Institute for Cancer Research, Université Catholique de Louvain, Brussels, Belgium. debacker@licr.ucl.ac.be
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De Backer
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Arden
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Boretti
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Vantomme
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De Smet
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Czekay
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Viars
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De Plaen
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Brasseur
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Chomez
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Van den Eynde
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Boon
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van der Bruggen
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D019556:COS Cells; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D000077209:Decitabine; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015723:Gene Library; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008969:Molecular Sequence Data; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D013737:Testis / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D014960:X Chromosome
D000951:Antigens, Neoplasm; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D000077209:Decitabine; D001374:Azacitidine