Disease relevance of XAGE1

• The XAGE family of cancer/testis-associated genes: alignment and expression profile in normal tissues, melanoma lesions and Ewing's sarcoma [1].
• RT-PCR studies showed frequent expression in melanoma metastases and Ewing's sarcoma for 2 XAGE-1-derived transcripts [1].
• Our previous expressed sequence tag database analysis indicates that XAGE-1 is frequently found in Ewing's sarcoma and alveolar rhabdomyosarcoma (U. Brinkmann et al., Cancer Res., 59: 1445-1448, 1999) [2].
• XAGE-1 and XAGE-2 are expressed in Ewing's sarcoma, rhabdomyosarcoma, a breast cancer, and a germ cell tumor [3].
• XAGE-1 expression in non-small cell lung cancer and antibody response in patients [4].

High impact information on XAGE1

• XAGE-1, a new gene that is frequently expressed in Ewing's sarcoma [2].
• Using Northern blots and RNA dot blots, we have now found that XAGE-1 is highly expressed in normal testis, in seven of eight Ewing's cell lines, in four of nine Ewing's sarcoma patient samples, and in one of one alveolar rhabdomyosarcoma patient sample [2].
• XAGE-1 and XAGE-2 should be evaluated as possible targets for vaccine-based therapies of cancer [3].
• Using a combination of cDNA subtraction and microarray analysis, we report here the identification and characterization of L552S, an over-expressed, alternatively spliced isoform of XAGE-1 in lung adenocarcinoma [5].
• This analysis revealed dense methylation of the CpG island in the XAGE-1 gene promoter for the normal and cancerous cells that do not express this gene but loss of this methylation in normal testis, cancer cell lines and the primary gastric cancers where the gene is highly expressed [6].

Biological context of XAGE1

• The XAGE family of cancer/testis-associated genes is located on chromosome Xp11.21-Xp11.22 [1].
• Interestingly, all GAGE-like genes contain a large secondary open reading frame, coding for putative proteins homologues to the XAGE-1 primary protein [1].
• To evaluate methylation as a potential mechanism for regulating expression of this gene, we first correlated gene methylation status (measured by sequencing of bisulfide-modified DNA and COBRA) to expression of XAGE-1 mRNA in normal and cancerous cells [6].
• The XAGE-1 gene consists of 4 exons and is located on chromosome Xp11.21-Xp11.22 [7].
• By serologic identification of antigens by recombinant expression cloning (SEREX) analysis using an autologous lung adenocarcinoma cell line, OU-LU-6, as a cDNA library source, we demonstrated that XAGE-1 was the dominant antigen recognized by serum from a patient [8].

Anatomical context of XAGE1

• Further supporting the role of methylation in regulating expression of XAGE-1 were observations that treatment of 2 heavily methylated cell lines, SNU620 and HT29, with 5'-aza-deoxycytidine resulted in demethylation of XAGE-1 promoter and corresponding expression of this gene [6].
• Finally, we cloned various segments of the CpG-rich XAGE-1 gene promoter linked to a luciferase reporter construct and transiently transfected this construct into HCT116 cells [6].

Regulatory relationships of XAGE1

• Collectively, these studies indicate that XAGE-1 expression in normal and cancerous tissues is regulated by methylation of the CpG island in the gene promoter [6].

Other interactions of XAGE1

• Three of these (NY-ESO-1, Lage-1, and Xage-1) were known members of the cancer/testis family of TAAs, and one other protein had previously been isolated by SEREX in cancer types other than PC [9].

Analytical, diagnostic and therapeutic context of XAGE1

• EXPERIMENTAL DESIGN: Forty-nine NSCLC specimens were analyzed for the expression of four XAGE-1 transcript variants by conventional 30-cycle and real-time reverse transcription-PCR and XAGE-1 protein expression by immunohistochemistry [4].
• Because XAGE-1 is expressed in such a diverse range of cancers, it has potential to be used as a target for many cancer immunotherapies [10].
• Genomic sequence analysis has revealed that L552S and XAGE-1 are alternatively spliced isoforms, and expression of both L552S and XAGE-1 isoforms are present in lung adenocarcinoma [5].
• The humoral response to XAGE-1 was investigated in sera obtained from 278 patients with prostate cancer and 40 healthy volunteers by enzyme-linked immunosorbent assay (ELISA) using recombinant protein [11].

References