Prognostic genetic markers in malignant gliomas

Glioblastomas are the most frequent andmalignant brain tumors in adults. Surgicalcure is virtually impossible and despite ofradiation and chemotherapy the clinicalcourse is very poor. Epigenetic silencing ofMGMT has been associated with a betterresponse to temozolomide-chemotherapy.We previously showed that temozolomideincreases the median survival time ofpatients with tumors harbouring deletionson 9p within the region for p15(INK4b),p16(INK4a), and 10q (MGMT).The aim of this study was to investigatethe methylation status of p15, p16, 14ARFand MGMT in glioblastomas and tocorrelate the results with the clinical data.Only patients with KPS > 70, radicaltumor resection, radiation andtemozolomide-chemotherapy afterrecurrence were included.We observed promoter methylation ofMGMT in 56% (15/27) and of p15 in 37%(10/27) of the tumors, whereas methylationof p16 and p14ARF were rare.Interestingly, methylation of p15emerged as a significant predictor of shorteroverall survival (16.9 vs. 23.8 months,p=0.025), whereas MGMT promotermethylation had no significant effect onmedian overall survival under thistreatment regimen (22.5 vs. 22.1 months,p=0.49). In the presence of other clinicallyrelevant factors, p15 methylation remainsthe only significant predictor (p=0.021;Cox regression).Although these results need to beconfirmed in larger series and underdifferent treatment conditions, ourretrospective study shows clear evidencethat p15 methylation can act as anadditional prognostic factor for survival andunderlines that this tumor suppressor,involved in cell cycle control, can act as anattractive candidate for therapeuticapproaches in glioblastomas.