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 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.
Hassel
J C
JC
Skin Cancer Unit, German Cancer Research Center, University Hospital Mannheim, Mannheim, Germany.
Sucker
A
A
Edler
L
L
Kurzen
H
H
Moll
I
I
Stresemann
C
C
Spieth
K
K
Mauch
C
C
Rass
K
K
Dummer
R
R
Schadendorf
D
D
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001483:Base Sequence; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D017931:DNA Primers; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D000077204:Temozolomide; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; D017931:DNA Primers; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide