Universität zu Köln

Hassel, J. C., Sucker, A., Edler, L., Kurzen, H., Moll, I., Stresemann, C., Spieth, K., Mauch, C., Rass, K., Dummer, R. and Schadendorf, D. (2010). MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome. Br. J. Cancer, 103 (6). S. 820 - 827. LONDON: NATURE PUBLISHING GROUP. ISSN 1532-1827

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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. British Journal of Cancer (2010) 103, 820-826. doi:10.1038/sj.bjc.6605796 www.bjcancer.com Published online 24 August 2010 (C) 2010 Cancer Research UK

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hassel, J. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sucker, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Edler, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kurzen, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Moll, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stresemann, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Spieth, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mauch, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rass, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dummer, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schadendorf, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-496662
DOI:	10.1038/sj.bjc.6605796
Journal or Publication Title:	Br. J. Cancer
Volume:	103
Number:	6
Page Range:	S. 820 - 827
Date:	2010
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1532-1827
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COOPERATIVE ONCOLOGY GROUP; METASTATIC MELANOMA; MALIGNANT-MELANOMA; PHASE-II; APOPTOSIS; HYPERMETHYLATION; GLIOBLASTOMA; COMBINATION; MULTICENTER; MANAGEMENT Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/49666