Expression spectrum and methylation-dependent regulation of melanoma antigen-encoding gene family members in pancreatic cancer cells.

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′-deoxycytid-ine 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.