gms | German Medical Science

Objective: The present study investigates the potential prognostic significance of various molecular parameters, including MGMT promoter methylation, MGMT sequence polymorphisms in exons 3 and 5, as well as MGMT protein expression, for progression free survival [PFS] and overall survival [OS] of patients with malignant gliomas. In addition, we determined the prognostic significance of loss of heterozygosity (LOH) on 1p and 19q, as well as aberrations in the TP53, CDK4, MDM2, PDGFRA and EGFR genes in the same patient series.

Methods: 95 patients, including 23 anaplastic gliomas of WHO grade III (AG) and 72 glioblastomas of WHO grade IV (GBM) were treated with temozolomide (≥3 cycles) as first line chemotherapy after tumor resection (no biopsies included) and radiation therapy. Acquired clinical data included i.a. age, Karnofsky score and tumorr volume (before and after resection, before chemotherapy and every 3 months), PFS and OS. The tumor tissue was investigated for hypermethylation of the MGMT promoter, six different MGMT sequence polymorphisms, immunohistochemical expression of MGMT protein, mutations in the TP53 gene (exons 5-9), amplification of the CDK4, MDM2, PDGFRA and EGFR genes, as well as LOH 1p and 19q. Molecular genetic findings were correlated to PFS and OS.

Results: Mean OS was 53 months (AG) and 20 months (GBM). Statistical analyses revealed that MGMT hypermethylation was significantly associated with longer PFS and OS in AG (p=0.02 and p<0.0001 respectively, log rank test [LRT]) and GBM (p=0.02 and p<0.0001 respectively, LRT). MGMT protein expression correlated with MGMT hypermethylation (chi-square test, p=0.03). The six investigated MGMT polymorphism were not associated with survival. In the AG group, LOH 1p was associated with longer OS (p=0.026) while TP53 mutation was associated with shorter PFS and OS (p=0.027 and p<0.036 respectively). Interestingly, 4 GBMs showed LOH on 1p but shorter PFS and OS as compared to GBMs with intact 1p.

Conclusions: Our study corroborates MGMT hypermethylation as a clinically important prognostic marker that correlates with longer PFS and OS in both AG and GBM patients. In contrast, the presence or absence of MGMT polymorphisms does not appear to be related to patient prognosis. LOH 1p and TP53 mutation were associated with prognosis in our group of AG patients. All other investigated genetic alterations do not appear to be of prognostic value in malignant glioma patients.