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

Abstract

Background:Despite limited clinical efficacy, treatment with dacarbazine or temozolomide (TMZ) remains the standard therapy for metastatic melanoma. In glioblastoma, promoter methylation of the counteracting DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT) correlates with survival of patients exposed to TMZ in combination with radiotherapy. For melanoma, data are limited and controversial.Methods:Biopsy samples from 122 patients with metastatic melanoma being treated with TMZ in two multicenter studies of the Dermatologic Cooperative Oncology Group were investigated for MGMT promoter methylation. We used the COBRA (combined bisulphite restriction analysis) technique to determine aberrant methylation of CpG islands in small amounts of genomic DNA isolated from paraffin-embedded tissue sections. To detect aberrant methylation, bisulphite-treated DNA was amplified by PCR, enzyme restricted, and visualised by gel electrophoresis.Results:Correlation with clinical data from 117 evaluable patients in a best-response evaluation indicated no statistically significant association between MGMT promoter methylation status and response. A methylated MGMT promoter was observed in 34.8% of responders and 23.4% of non-responders (P=0.29). In addition, no survival advantage for patients with a methylated MGMT promoter was detectable (P=0.79). Interestingly, we found a significant correlation between MGMT methylation and tolerance of therapy. Patients with a methylated MGMT promoter had more severe adverse events, requiring more TMZ dose reductions or discontinuations (P=0.007; OR 2.7 (95% CI: 1.32–5.7)). Analysis of MGMT promoter methylation comparing primaries and different metastases over the clinical course revealed no statistical difference (P=0.49).Conclusions:In advanced melanoma MGMT promoter, methylation correlates with tolerance of therapy, but not with clinical outcome.

Dacarbazine in Solitary Fibrous Tumor: A Case Series Analysis and Preclinical Evidence vis-à-vis Temozolomide and Antiangiogenics

“…In fact, it is known that in glioblastoma the presence of MGMT promoter methylation--that enhances the response to alkylating agents by inhibiting DNA repair-is predictive of a better response to temozolomide in combination with radiotherapy (17). On the contrary, MGMT predictive role has not been definitively confirmed in other tumors responsive to temozolomide such as melanoma (30). The correlation between MGMT gene methylation status and the response to dacarbazine and temozolomide can thus represent an interesting field of research in SFT.…”

Epigenetic regulation in human melanoma: past and future

“…23 Primary and metastatic melanoma were compared in order to identify differences in MGMT methylation status, but no such differences were found. 31 This could be explained by the finding in various types of cancer that histone 3 lysine 9 (H3K9) dimethylation and MeCP2 binding are common and essential for MGMT silencing regardless of DNA methylation status at the promoter CpG island. 32 This emphasizes that functional characterization of hypermethylated genes identified in melanoma is essential and that the methylation status of a gene may not necessarily serve as a suitable marker for tracking the progression of melanoma.…”

O 6 -methylguanine DNA methyltransferase gene promoter methylation in high-grade gliomas: A review of current status

“…Combined bisulfite restriction analysis (COBRA) utilizes restriction endonucleases that recognize DNA methylation at specific sites (Hassel et al). [46] Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is a semiquantitative assay in which troublesome bisulfite conversion of unmethylated cytosines can be omitted. [36] Methylationsensitive high-resolution melting (MS-HRM) allows for estimation of the methylation level by comparing the melting profiles of unknown PCR products to the melting profiles of PCR products derived from standards with a known unmethylated to methylated template ratio.…”