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

Abstract

Tumor spread to distant organs is the most serious consequence of melanoma, as only 10-20% of stage IV patients respond to current chemotherapies. Tumor sensitivity to alkylating agents is affected by the activity of cellular DNA repair proteins, such as O(6)-methylguanine DNA methyltransferase (MGMT) and the DNA mismatch repair proteins. Chemosensitivity may be enhanced by reduced MGMT activity, but the frequency of MGMT promoter silencing through hypermethylation is unknown in distant melanoma metastases. The frequency and significance of microsatellite instability (MSI) in metastatic melanoma is also unclear, and it has been suggested that MSI frequency increases during the metastatic process. We undertook an analysis of 84 melanoma metastases from 47 patients. MGMT methylation was detected using methylation-specific PCR in 26 of 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 of chemosensitivity. High MSI involving mononucleotide repeat markers was not found. Low MSI was detected in five of 50 metastases (10%) and only one of the five metastases also had MGMT methylation. These results demonstrate that in contrast to some previous reports, these tumors have a low frequency of MSI.

MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome

“…In agreement with this interpretation, we found no significant differences between the MGMT methylation status of melanoma primaries or metastases in 65 patients with up to 9 metastases. This confirms the findings of Rastetter et al (2007) but is in contrast with those of Kohonen-Corish et al (2006) who described heterogeneity in MGMT gene methylation between melanoma metastases from the same patient for a limited number of 11 patients.…”

Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents

“…Although AGT protects cells against the cytotoxic effects of methylating agents, cell death in response to methylating agents actually occurs as a consequence of the MMR pathway, whereby unrepaired O 6 MG residues pair with thymines during replication triggering a futile cycle of the MMR pathway and ultimately cell death. However, as deficiency in the MMR pathway occurs infrequently in melanoma (26), it is unlikely to contribute to temozolomide resistance in our system. A recent report implicated the base excision repair pathway as a major contributor to cellular resistance to temozolomide showing that temozolomide efficacy is dependent on expression and activity of specific base excision repair genes (27).…”

Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma

“…Such intra-individual heterogeneity has also been reported for metastases from skin melanoma. 16 However, we cannot exclude that these differences are based on artifacts due to sampling errors and the small diameter of the tissue cores (2 mm in diameter) on the TMA.…”

“…[13][14][15][16][17] No data are yet available on MGMT in uveal melanoma in the literature. Herein, we investigated the frequency of the epigenetic silencing of MGMT gene in liver metastases from uveal melanoma patients.…”

“…13 Although the results and the sample size in the studies reported are generally small and heterogeneous, there seems to be an increase in frequency of MGMT-promoter methylation during tumor progression from 10% in primary melanomas to 30% in metastases. [13][14][15][16][17] No data are yet available on MGMT in uveal melanoma in the literature. Herein, we investigated the frequency of the epigenetic silencing of MGMT gene in liver metastases from uveal melanoma patients.…”