gms | German Medical Science

Objective: The N-myc downregulated gene (NDRG) family is a largely unstudied group of genes that have predominantly tumor suppressive effects. NDRG induction occurs via hypoxia, cellular differentiation, by N-myc activation or in neoplasia. Pathway components are overexpressed in many tumors including glioblastoma (GBM). Previous studies showed that NDRG4 is up-regulated in GBM compared to normal human brain tissue and knock-down of NDRG4 reduced the viability of GBM cells. In our study, we investigate the expression of two NDRG family components, NDRG2 and NDRG4, in glioblastoma specimens and normal brain tissue and correlate these data with progression-free survival after combined radiochemotherapy and MGMT methylation

Method: Samples from 44 patients (31 males, 13 females, age 57.4 ± 15.7 years) suffering from primary (n=40) and secondary (n=4) glioblastoma were quantified using quantitative real-time PCR and immunohistochemistry (by a dimensionless semiquantitative immunoreactivity score, IRS, ranging from 0-12) for NDRG2 and NDRG4. Ten non-tumorous autopsy brain specimens were used as controls. Expression data was correlated with clinical data and progression-free survival (PFS).

Results: At the protein level, NDRG2 was significantly down-regulated in glioblastoma (IRS in non-tumorous white matter 8.8 ± 3.3 vs. 3.5 ± 3.0 in glioblastoma, p=0.003) while NDRG4 was significantly up-regulated (white matter 0.75 ± 0.4 vs. 5.4 ± 3.7, p<0.001 in glioblastoma). In patients with primary glioblastoma with MGMT methylation for which samples were obtained at the 1st surgery (subset of 10 patients) treated with adjuvant radiochemotherapy (temozolomide and 60 Gy radiotherapy), we observed differences in the progression-free survival based on NDRG4 mRNA expression: patients with low levels of NDRG4 (defined as expression levels equal or below the mean expression in our glioblastoma study group) had a median PFS of 6 months (95% CI 0.1 - 11.9) vs. 21 months (95% CI 10.2 - 31.8) in patients with high NDRG4 levels (above mean expression in the tumors) (p=0.017).

Conclusions: NDRG2 and NDRG4 expression in glioblastoma patients is significantly altered when compared to non-tumorous brain tissue. PFS in MGMT-methylated patients with primary glioblastoma treated with combined radiochemotherapy differed in the low/high NDRG4 expression groups. These data warrant further functional studies and confirmation in a larger patient study group, as they suggest that NDRG4 expression influences PFS in glioblastoma patients.