Authors: Jonathon F Parkinson Helen R Wheeler Adele Clarkson Catriona A McKenzie Michael T Biggs Nicholas S Little Raymond J Cook Marinella Messina Bruce G Robinson Kerrie L McDonald
Publish Date: 2007/11/15
Volume: 87, Issue: 1, Pages: 71-78
Abstract
Methylation of the promoter region of the O 6 methylguanineDNA methyltransferase MGMT gene is known to be predictive of response to temozolomide treatment in patients with glioblastoma Contrastingly little is known about variation in the methylation status of the MGMT promoter after treatment or across different regions of the same tumor About 22 samples from 10 patients who had undergone multiple resections of a glioblastoma were examined with promoter sequencing Of these 20 were also analyzed using Methylation Specific PCR MSP The methylation status of the MGMT promoter was altered in the specimens obtained pre and post treatment in 2 of 9 samples as assessed by MSP and 7 out of 10 patients as assessed by promoter sequencing In four patients the MGMT promoter was unmethylated at primary surgery but displayed some methylation 32 44 12 and 4 on posttreatment sampling Alteration in MSP status from unmethylated to methylated was also observed in 2 of these 4 patients In another patient methylation increased from 40 on initial sampling to 68 on the second sample The remaining two patients initially demonstrated some degree of methylation 72 and 12 subsequent sampling showed no methylation of the MGMT promoter To ensure variable methylation status was not due to intratumoral variability three to four specimens were sampled from different regions of large glioblastomas n = 7 Promoter sequencing revealed minimal variation in methylation in all but two sites examined Immunohistochemistry also demonstrated minimal change in MGMT expression across the tumors This suggests that variation in MGMT promoter methylation can occur within the same tumor after treatment necessitating caution in clinical decisionmaking based on this analysis
Keywords: