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MGMT promoter methylation is associated with temozolomide response and prolonged progression-free survival in disseminated cutaneous melanoma.
- Source :
-
International journal of cancer [Int J Cancer] 2015 Jun 15; Vol. 136 (12), pp. 2844-53. Date of Electronic Publication: 2014 Nov 24. - Publication Year :
- 2015
-
Abstract
- To investigate the predictive and prognostic value of O(6) -methylguanine DNA methyltransferase (MGMT) inactivation by analyses of promoter methylation in pretreatment tumor biopsies from patients with cutaneous melanoma treated with dacarbazine (DTIC) or temozolomide (TMZ) were performed. The patient cohorts consisted of Belgian and Swedish disseminated melanoma patients. Patients were subdivided into those receiving single-agent treatment with DTIC/TMZ (cohort S, n = 74) and those treated with combination chemotherapy including DTIC/TMZ (cohort C, n = 79). Median follow-up was 248 and 336 days for cohort S and cohort C, respectively. MGMT promoter methylation was assessed by three methods. The methylation-related transcriptional silencing of MGMT mRNA expression was assessed by real-time RT-PCR. Response to chemotherapy and progression-free survival (PFS) and overall survival were correlated to MGMT promoter methylation status. MGMT promoter methylation was detected in tumor biopsies from 21.5 % of the patients. MGMT mRNA was found to be significantly lower in tumors positive for MGMT promoter methylation compared to tumors without methylation in both treatment cohorts (p < 0.005). DTIC/TMZ therapy response rate was found to be significantly associated with MGMT promoter methylation in cohort S (p = 0.0005), but did not reach significance in cohort C (p = 0.16). Significantly longer PFS was observed among patients with MGMT promoter-methylated tumors (p = 0.002). Multivariate Cox regression analysis identified presence of MGMT promoter methylation as an independent variable associated with longer PFS. Together, this implies that MGMT promoter methylation is associated with response to single-agent DTIC/TMZ and longer PFS in disseminated cutaneous melanoma.<br /> (© 2014 UICC.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Cohort Studies
Dacarbazine administration & dosage
Dacarbazine therapeutic use
Disease-Free Survival
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Male
Melanoma genetics
Melanoma pathology
Middle Aged
Outcome Assessment, Health Care methods
Outcome Assessment, Health Care statistics & numerical data
Prognosis
Proportional Hazards Models
Reverse Transcriptase Polymerase Chain Reaction
Skin Neoplasms
Temozolomide
Melanoma, Cutaneous Malignant
DNA Methylation
Dacarbazine analogs & derivatives
Melanoma drug therapy
O(6)-Methylguanine-DNA Methyltransferase genetics
Promoter Regions, Genetic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0215
- Volume :
- 136
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 25400033
- Full Text :
- https://doi.org/10.1002/ijc.29332