O6-Methylguanine DNA methyltransferase expression in tumor cells predicts outcome of radiotherapy plus concomitant and adjuvant temozolomide therapy in patients with primary glioblastoma

Abstract

Expression of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene has been shown to correlate with clinical outcomes in patients with glioblastoma multiforme treated with alkylating agents. We evaluated MGMT protein expression in 53 primary glioblastomas by the immunohistochemistry (IHC) and analyzed the correlation between results of immunostaining and patient outcomes. There were 28 MGMT-immunopositive and 25 negative glioblastomas. Patients with MGMT-immunonegative glioblastomas showed significantly longer progression-free survival (PFS) (P = 0.0032), but no statistically significant benefits on overall survival (OS) (P = 0.0825) were shown. In 41 glioblastomas treated with temozolomide (TMZ) therapy (MGMT-immunopositive: n = 22, negative: n = 19), both PFS and OS were significantly better in MGMT-immunonegative glioblastomas. (PFS: P = 0.0015, OS: P = 0.0384). We conclude that MGMT expression on immunohistochemistry (IHC) correlates with outcomes in patients with primary glioblastoma receiving TMZ and suggest the use of MGMT-IHC as a surrogate marker for predicting tumor chemosensitivity.

Novel approaches for quantifying protein biomarkers in gliomas: benefits and pitfalls

“…Upregulated upon cell activation Cytoplasm [43] JAM-A Cell-cell adhesion protein expressed in brain tumor stem-like cells Cytoplasm, membrane [27,28] Ki-67 Protein expressed in proliferative cells during the active phases of the cell cycle Nucleus [22][23][24] MGMT Ubiquitously expressed DNA repair protein, removing methylation at the O 6 -position of guanine Nucleus [10,45,46,[48][49][50][51][52] Musashi-1 Neural RNA-binding protein expressed by neural stem cells/progenitor cells and brain tumor stem-like cells Ki-67 [22][23][24] and the hypoxia inducible factor HIF1α [25,26] provide examples of nuclear markers expressed in glioma tissue or glioma spheroids, which can be detected by such trained classifiers (Figure 2a-D).…”

“…Membrane [44,45] c-Met Receptor tyrosine kinase involved in tumor growth and angiogenesis Cytoplasm, membrane [29][30][31] GLUT1 Protein facilitating transport of glucose across the plasma membrane…”

CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains

“…Immunohistochemical staining was performed as previously described (35). An anti-PDPN mAb (1:5,000, clone NZ-1.2, rat IgG 2a ) was used to detect PDPN.…”

Temozolomide with or without Radiotherapy in Patients with Newly Diagnosed Glioblastoma Multiforme: A Meta-Analysis

“…Similarly, the TMZ-induced enhanced radiation response is shown to be due to an increased degree of radiation-induced double-strand DNA damage, which is more prominent in MGMT-negative glioblastomas [27]. Several reports indicate that methylation of the MGMT promoter is the strongest predictor of outcome and benefit in TMZ chemotherapy [6,12,18,28,29]. …”