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

Hassel JC, Sucker A, Edler L, Kurzen H, Moll I, Stresemann C, Spieth K, Mauch C, Rass K, Dummer R, Schadendorf D - Br. J. Cancer (2010)

Bottom Line: 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.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)).

View Article: PubMed Central - PubMed

Affiliation: Skin Cancer Unit, German Cancer Research Center, University Hospital Mannheim, Mannheim, Germany.

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 O(6)-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.

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O6-methylguanine-DNA-methyltransferase expression by immunohistology in melanoma metastases with MGMT promotor methylation status analysed by COBRA. (A) COBRA analysis suggested unmethylated MGMT promotor; (B) or a methylated MGMT promotor. In comparision as positive staining control a colonic cancer biopsy was chosen (C). The immunohistochemical staining was carried out on paraffin-embedded tissue using a monoclonal anti-MGMT antibody and a Polymer-based Permanent AP Red Kit. Slides were shortly counterstained with Hämalaun.
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fig2: O6-methylguanine-DNA-methyltransferase expression by immunohistology in melanoma metastases with MGMT promotor methylation status analysed by COBRA. (A) COBRA analysis suggested unmethylated MGMT promotor; (B) or a methylated MGMT promotor. In comparision as positive staining control a colonic cancer biopsy was chosen (C). The immunohistochemical staining was carried out on paraffin-embedded tissue using a monoclonal anti-MGMT antibody and a Polymer-based Permanent AP Red Kit. Slides were shortly counterstained with Hämalaun.

Mentions: In addition to MGMT promoter methylation, we examined several tissue samples for MGMT protein expression levels by immunohistochemistry. O6-methylguanine-DNA-methyltransferase expression was very low in all the melanoma samples tested, irrespective of the MGMT promoter methylation status determined or clinical outcome (Figure 2, Supplementary Table 2).


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

Hassel JC, Sucker A, Edler L, Kurzen H, Moll I, Stresemann C, Spieth K, Mauch C, Rass K, Dummer R, Schadendorf D - Br. J. Cancer (2010)

O6-methylguanine-DNA-methyltransferase expression by immunohistology in melanoma metastases with MGMT promotor methylation status analysed by COBRA. (A) COBRA analysis suggested unmethylated MGMT promotor; (B) or a methylated MGMT promotor. In comparision as positive staining control a colonic cancer biopsy was chosen (C). The immunohistochemical staining was carried out on paraffin-embedded tissue using a monoclonal anti-MGMT antibody and a Polymer-based Permanent AP Red Kit. Slides were shortly counterstained with Hämalaun.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2966614&req=5

fig2: O6-methylguanine-DNA-methyltransferase expression by immunohistology in melanoma metastases with MGMT promotor methylation status analysed by COBRA. (A) COBRA analysis suggested unmethylated MGMT promotor; (B) or a methylated MGMT promotor. In comparision as positive staining control a colonic cancer biopsy was chosen (C). The immunohistochemical staining was carried out on paraffin-embedded tissue using a monoclonal anti-MGMT antibody and a Polymer-based Permanent AP Red Kit. Slides were shortly counterstained with Hämalaun.
Mentions: In addition to MGMT promoter methylation, we examined several tissue samples for MGMT protein expression levels by immunohistochemistry. O6-methylguanine-DNA-methyltransferase expression was very low in all the melanoma samples tested, irrespective of the MGMT promoter methylation status determined or clinical outcome (Figure 2, Supplementary Table 2).

Bottom Line: 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.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)).

View Article: PubMed Central - PubMed

Affiliation: Skin Cancer Unit, German Cancer Research Center, University Hospital Mannheim, Mannheim, Germany.

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 O(6)-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.

Show MeSH
Related in: MedlinePlus