Promoter Hypermethylation of the O6-Methylguanine DNA Methyltransferase Gene and Microsatellite Instability in Metastatic Melanoma

Tumor spread to distant organs is the most serious consequence of melanoma, as only 10–20% of stage IVpatients respond to current chemotherapies. Tumor sensitivity to alkylating agents is affected by the activity ofcellular DNA repair proteins, such as O6-methylguanine DNA methyltransferase (MGMT) and the DNAmismatch repair proteins. Chemosensitivity may be enhanced by reduced MGMT activity, but the frequency ofMGMT promoter silencing through hypermethylation is unknown in distant melanoma metastases. Thefrequency and significance of microsatellite instability (MSI) in metastatic melanoma is also unclear, and it hasbeen suggested that MSI frequency increases during the metastatic process. We undertook an analysis of 84melanoma metastases from 47 patients. MGMT methylation was detected using methylation-specific PCR in 26of the 84 metastases (31%), but there was discordance between individual metastases from the same patient.Therefore, as a result of this variation, MGMT methylation may have only limited value as a predictor ofchemosensitivity. High MSI involving mononucleotide repeat markers was not found. Low MSI was detected infive of 50 metastases (10%) and only one of the five metastases also had MGMT methylation. These resultsdemonstrate that in contrast to some previous reports, these tumors have a low frequency of MSI.