Impact of Oncogenic Alterations on MGMT Promoter Methylation Status in Glioblastoma (GBM)
Yuan Rong, Cristina Vincentelli, Candace Chisolm, Jeffrey J Olson, Charlie Hao, Stephen B Hunter, Daniel J Brat. Emory University School of Medicine, Atlanta, GA
Background: GBM is the most common primary malignant brain tumor and consists of multiple genetic subtypes. O6 – methylguanine – DNA methyltransferase (MGMT) is a key DNA repair enzyme that antagonizes chemotherapy-induced DNA crosslinking at the O6 position of guanine. MGMT promoter methylation, found in ∼ 40% GBMs, is associated with reduced MGMT expression, enhanced response to temozolomide and improved survival. Here we investigate correlations between specific genetic alterations and MGMT promoter methylation in GBM.
Design: Results of molecular testing on 120 primary GBMs diagnosed from 2008 to 2010 at Emory University were analyzed. Methylation of the MGMT promoter was determined by methylation-specific PCR. EGFR amplification (amp) and PTEN deletion (del) were detected by fluorescence in situ hybridization (FISH). Immunohistochemistry was used to detect mutant IDH1 expression (IDH1R132H).
Results: Among GBMs in this study, MGMT promoter methylation was detected in 55 of 120 (46%); EGFR amp in 45 of 120 (38%); PTEN del in 72 of 78 (92%); both EGFR amp and PTEN del in 27 of 73 (37%); and IDH1 mutation in 13 of 109 (12%). MGMT promoter methylation was present in 25 of 45 (56%) cases with EGFR amp and in 25 of 75 (33%) with wt EGFR (Fisher's exact test, p < 0.05); 34 of 72 cases (47%) with PTEN loss and in 3 of 6 (50%) with PTEN intact; and in 19 of 27 (70%) with both EGFR amplification and PTEN loss (p < 0.05). MGMT promoter methylation was present in 9 of 13 (69%) cases with mutant IDH1 protein detected and in 44 of 96 (46%) without mutant IDH1 detected (p = 0.1).
Conclusions: Our results indicate that MGMT promoter methylation is most frequent in those GBMs with EGFR amplification and IDH1 mutation.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 246, Tuesday Afternoon