p15 promoter methylation - a novel prognostic marker in glioblastoma patients.

Glioblastomas are the most frequent and malignant brain tumors in adults. Surgical cure is virtually impossible and despite radiation and chemotherapy the clinical course is very poor. Epigenetic silencing of MGMT has been associated with a better response to temozolomide-chemotherapy. We previously showed that temozolomide increases the median survival time of patients with tumors harbouring deletions on 9p within the region for p15(INK4b), p16(INK4a), and 10q (MGMT). The aim of this study was to investigate the methylation status of p15, p16, p14ARF and MGMT in glioblastomas (n=27) and to correlate the results with the clinical data. Only patients with KPS >70, radical tumor resection, radiation and temozolomide-chemotherapy after recurrence were included. We observed promoter methylation of MGMT in 56% and of p15 in 37% of the tumors, whereas methylation of p16 and p14ARF were rare. Interestingly, methylation of p15 emerged as a significant predictor of shorter overall survival (16.9 vs. 23.8 months, p=0.025), whereas MGMT promoter methylation had no significant effect on median overall survival under this treatment regimen (22.5 vs. 22.1 months, p=0.49). In the presence of other clinically relevant factors, p15 methylation remains the only significant predictor (p=0.021). Although these results need to be confirmed in larger series as well as under different treatment conditions, our retrospective study shows clear evidence that p15 methylation is an important prognostic factor for survival and underlines that this tumor suppressor, involved in cell cycle control, is an attractive candidate for therapeutic approaches in glioblastomas.