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

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...

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Autores principales: Hassel, J C, Sucker, A, Edler, L, Kurzen, H, Moll, I, Stresemann, C, Spieth, K, Mauch, C, Rass, K, Dummer, R, Schadendorf, D
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2966614/
https://www.ncbi.nlm.nih.gov/pubmed/20736948
http://dx.doi.org/10.1038/sj.bjc.6605796
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author Hassel, J C
Sucker, A
Edler, L
Kurzen, H
Moll, I
Stresemann, C
Spieth, K
Mauch, C
Rass, K
Dummer, R
Schadendorf, D
author_facet Hassel, J C
Sucker, A
Edler, L
Kurzen, H
Moll, I
Stresemann, C
Spieth, K
Mauch, C
Rass, K
Dummer, R
Schadendorf, D
author_sort Hassel, J C
collection PubMed
description 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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spelling pubmed-29666142011-09-07 MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome Hassel, J C Sucker, A Edler, L Kurzen, H Moll, I Stresemann, C Spieth, K Mauch, C Rass, K Dummer, R Schadendorf, D Br J Cancer Translational Therapeutics 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. Nature Publishing Group 2010-09-07 2010-08-24 /pmc/articles/PMC2966614/ /pubmed/20736948 http://dx.doi.org/10.1038/sj.bjc.6605796 Text en Copyright © 2010 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Translational Therapeutics
Hassel, J C
Sucker, A
Edler, L
Kurzen, H
Moll, I
Stresemann, C
Spieth, K
Mauch, C
Rass, K
Dummer, R
Schadendorf, D
MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome
title MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome
title_full MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome
title_fullStr MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome
title_full_unstemmed MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome
title_short MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome
title_sort mgmt gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2966614/
https://www.ncbi.nlm.nih.gov/pubmed/20736948
http://dx.doi.org/10.1038/sj.bjc.6605796
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