PURPOSE/OBJECTIVE The molecular responses of glioblastomas (GBMs) to hypofractionated IMRT/TMZ were investigated to elucidate the molecular targets included in the resistance of these tumors to chemo-radiation therapy. MATERIALS /METHODS Phase I study of neo-adjuvant IMRT (72Gy/12Fx.)/TMZ for the treatment of patients with GBMs had been performed previously in our institution. In this trial, stereotactic biopsy of the tumor to confirm the pathological diagnosis prior to treatment was required, and tumor removal was scheduled within 10 days after completion of IMRT/TMZ. Therefore, both the tumor samples before and immediately after IMRT/TMZ were available. By comparing the gene expression profiles before and after IMRT/TMZ using the total mRNA sequencing (RNAseq) analysis, molecular responses of GBMs against IMRT/TMZ were investigated. More than two-fold change of expression levels was defined as significant. RESULTS Tumor sample sets from five patients with GBMs were investigated. Among the 17,532 genes evaluated, 35 genes were found to show significant changes in gene expression in all cases, and 450 genes in more than half of the cases. Among the DNA repair related genes, DDB2 was the only gene that showed significant up-regulation in all cases. On the other hand, among the cell cycle checkpoint related genes, gene expressions of CKD1/CCNB were decreased in all cases. Although the expression of TP53 was not changed, the expressions of CDKN1A/GADD45/Reprimo/SFN were also reduced. Moreover, although the expression change of CHK1 was not found, the expressions of CDC25/PLK1/AURKA were decreased in more than half of the cases. From these results, it was considered that GBM arrested the cell cycle at the G2/M checkpoint without regulation of TP53 or CHK1 after IMRT/TMZ. CONCLUSIONS Our results suggested that cell cycle arrest in G2/M plays a significant role in survival of GBM cells after IMRT/TMZ.
