gms | German Medical Science

Objective: Glioblastomas are the most frequent and malignant tumors of the central nervous system. Surgical cure is virtually impossible and the clinical course is mainly determined by the biological behaviour of the tumor cells and their response to radiation and chemotherapy. MGMT promotor hypermethylation was shown to be a prognostic parameter for TMZ response. We were also able to show that TMZ increases the median survival time of patients with tumors harbouring deletions on 9p with the loci for CDKN2A (p16, p14^ARF) and CDKN2B (p15). Therefore, the aim of our current study was to investigate the role of the methylation status of p15, p16 and p14^ARF in addition to MGMT methylation status and correlate these results with the clinical data.

Methods: DNA was isolated from fresh frozen GBM biopsies (n=22), and modified by sodium bisulfite. Methylation-specific polymerase chain reaction (MS-PCR) was performed to analyze the methylation status of MGMT, p15, p16 and p14^ARF and the results were correlated to the overall survival time. All patients were treated with radiotherapy and TMZ chemotherapy after radical tumor resection. Only patients with a good Karnofsky Score (>70) were included.

Results: We observed methylation of the MGMT promotor in 59% (13/22) and of p15 in 32% (7/22) of the tumors, whereas methylation of p16 and p14^arf plays no important role in these tumors (5% and 0%, respectively). Overall survival time of patients with methylated MGMT was 26 months compared to 22 months of patients with unmethylated MGMT. Interestingly, patients with methylated p15 showed a drastic decrease in survival time compared to unmethylated p15 (16 vs. 30 months). Patients harbouring methylation of p15 and MGMT had a survival time comparable of those with only methylated p15, whereas patients with a methylated MGMT and unmethylated p15 showed the best prognosis under TMZ (33 months).

Conclusions: Our retrospective study showed that patients with tumors exhibiting methylated MGMT and unmethylated p15 benefit most from TMZ therapy, whereas the methylation of p15 might act as an marker for a poorer clinical course.