Concordance Rates of O(6)-Methylguanine DNA-Methyltransferase Promoter Methylation in Primary-Recurrent Paired Glioblastoma Samples.
Aditya Raghunathan, Kristin L Diefes, Lindsey Heathcock, Suzanne Z Powell, Gregory N Fuller, Kenneth D Aldape. University of Texas M.D. Anderson Cancer Center, Houston; The Methodist Hospital, Houston, TX
Background: O(6) methylguanine DNA-methyltransferase (MGMT) is a mechanism of resistance for glioblastoma cells against alkylating and methylating chemotherapeutic agents. Glioblastomas lacking MGMT expression are more sensitive to these agents. The MGMT promoter methylation at CpG islands leads to MGMT silencing, and can be detected as a potential predictive test. Changes in MGMT methylation status during radiation and chemotherapy might influence response to therapy.
Design: Patients with glioblastoma who had undergone radiation and chemotherapy, and were subsequently diagnosed with residual/ recurrent disease were identified. Representative formalin-fixed paraffin-embedded (FFPE) tissue blocks were selected from the initial and subsequent surgical specimens. MGMT methylation status was determined by methylation-specific PCR (MSP), performed in triplicate, while blinded as to any clinical data.
Results: There were 7 males and 2 females, 34 to 66 years old (mean 52 yrs) At initial diagnosis. All underwent surgical resection, radiation therapy of up to 60 Gy, and chemotherapy with temozolomide. Residual/ recurrent disease was diagnosed at 2 to 45 months (mean 19.6 months) from initial diagnosis. Seven patients survived 9 to 46 months (mean 23.8 months) to last contact, while 2 died of glioblastoma, confirmed on autopsy.
Seven cases retained MGMT-promoter methylation status in initial and subsequent specimens, as methylated (MGMT-M) in 2/9 (22%) and unmethylated (MGMT-U) in 5/9 (56%). One case initial MGMT-M and subsequent MGMT-U. A second case had initial MGMT-U and subsequent MGMT-M. These two cases were 34 and 36 years old (compared to 57 years in retained status), recurred at 17 and 18 months (compared to 20 months in retained status), and survived 17 and 18 months from initial diagnosis (compared to 25.5 months in retained status), with one dying of disease and one alive with disease at last contact. In this study, we did not find any significant association between initial and subsequent MGMT-promoter methylation status.
Conclusions: While majority of glioblastomas appear to retain their MGMT- promoter methylation status even after radiation and chemotherapy, these data suggest that the methylation status can change in a small proportion of glioblastomas. It has been reported that MSP in FFPE tissue may lack of reproducibility in a proportion of samples. It is possible that technical issues are responsible for our discordant cases. Further work is required to examine this more fully.
Tuesday, March 1, 2011 2:00 PM
Platform Session: Section G, Tuesday Afternoon