MGMT PROMOTER HYPERMETHYLATION AND P53 IMMUNOHISTOCHEMISTRY PREDICT OUTCOME FOLLOWING TEMOZOLOMIDE FOR RECURRENT 1P/19Q NON-DELETED ANAPLASTIC (OLIGO)ASTROCYTOMA

Background: Tumor specific molecular-genetic features determine the prognosis and sensitivity to alkylating agents of central nervous system gliomas. The O6-methylguanine-DNA-methyltransferase (MGMT) gene promoter is often hypermethylated in high-grade gliomas (HGG) and is a major determinant of the sensitivity to alkylating agents. The tumor suppressor gene p53 is a frequent target for mutation but its importance as a prognostic or predictive marker has not been established. We investigated the correlation between MGMT methylation status and p53 immunohistochemical staining and the benefit from treatment with temozolomide in patients with recurrent HGG.
Patients and Methods: A real-time, quantitative methylation-specific PCR (QMSP) assay for the determination of the MGMT promoter methylation status and immunohistochemical staining for p53 TSG were performed on archival tissue blocks from 38 glioma patients (22 with glioblastoma, 12 with anaplastic astrocytoma [AA], and 4 with anaplastic oligoastrocytoma [AOA], treated with temozolomide at first recurrence. In addition we performed fluorescence in situ hybridization for the characterization of chromosomal loss of 1p, 19q and the 17p13.1 locus (p53) and for gains of the EGFR locus.
Results: WHO differentiation grade, MGMT methylation status were significantly correlated with time to progression following temozolomide at first recurrence (Cox logistic regression analysis). Within the subgroups of grade III and IV glioma, significance for these two baseline variables was only observed for patients with anaplastic (oligo)astrocytoma. In this subgroup, as opposed to glioblastoma patients, TP53 IHC positivity more strongly predicted a favourable TTP. None of these 16 anaplastic gliomas had loss of 1p or 19q or amplification of EGFR. MGMT promoter methylation correlated with superior overall survival following temozolomide in patients with AA/AOA but not glioblastoma.
Conclusions: The synchronous presence of both MGMT promoter methylation and p53 IHC status appear to be useful molecular markers to predict favourable survival following temozolomide at recurrence only in patients with anaplastic oligoastrocytoma without 1p/19q loss or EGFR amplification.