Promoter methylation of MGMT in paired primary and recurrent glioblastomas.

Abstract

10543 Background: Epigenetic sliencing of MGMT gene promoter in primary glioblastomas (GBM) of pts subsequently treated with temozolomide (TMZ) is associated with prolonged survival. Further, several studies have observed a change in MGMT silencing in paired primary and recurrent GBM. However, the relationship between this “MGMT switch” and patients outcome is largely unknown. Methods: The study involved primary and recurrent tumor tissue samples from 53 GBM pts diagnosed and treated within the First Hospital of Jilin University from Jan 2003 to Nov 2010. After surgical treatment, all pts were subjected to radiotherapy with concomitant administration of TMZ (75 mg/m2/d), followed by 5 cycles of adjuvant TMZ given at 4-weeks intervals. Pts that experienced recurrent tumors received TMZ at a dose of 200 mg/m2/5 days for 4 weeks. 53 pts underwent 58 further operations after recurrence (5 pts received a third surgery). MGMT promoter methylation levels were determined using qMSP. The relationship between “MGMT switch” and clinical outcome was investigated. Results: Fifty three (M/F=33/20; median age: 49.2±3.6, range: 19.5-72.3 ys) underwent a first operation for GBM. qMSP analysis revealed MGMT promoter methylation in 19 pts (35.8%, group A, OS 31.5 ms); no methylation in 34 pts (64.2%, group B, OS 7.9 ms). In the recurrent tumors, MGMT promoter methylation was detected in 25 pts (47.2%); and no methylation in 28 pts (52.8%). Comparison of individual pairs of primary and recurrent GBMs revealed a changed methylation status in 10 (18.9%), including eight changed from unmethylated to methylated tumors (15.1%, group C, OS 29.4 ms), two changed from methylated to unmethylated tumors (3.8%, group D, OS 10.5 ms). Median overall survival was 12.1 ms. MGMT promoter methylation was significantly associated with a favorable clinical outcome (group A vs group B, p=0.0027). The outcome of pts were not significant different between A and C (p>0.01). Conclusions: The methylation status of the MGMT promoter was altered in 10 (18.9%) of 53 recurrent GBM after chemoradiotherapy. Eight pts changed from unmethylated to methylated who have a median overall survival similar to methylated pts. The pts changed from methylated to unmethylated who have poor outcome.