| Section One: Classification based on mutations of TERT promoter and IDH characterizes subtypes in grade II/IIIglioma Background Grade II and III gliomas have variable clinical behaviors, showing the distinct molecular genetic alterations from glioblastoma(GBM), many of which eventually transform into more aggressive tumors. Since the classifications of grade II/III gliomas based on the genetic alterations have been recently emerging, it is now a trend to include molecular data into the stan- dard diagnostic algorithm of glioma. Methods Here we sequenced TERT promoter mutational status(TERTp-mut) in the DNA of 377 grade II/III gliomas and analyzed the clinical factors, molecular aberrations, and transcriptome profiles. Results We found that TERTp-mut occurred in 145 of 377 grade II and III gliomas(38.5%), mutually exclusive with a TP53 mu- tation(TP53-mut; P,.001) and coincident with a 1p/19 q co-deletion(P 1?4.002). TERTp-mut was an independent predictive factor of a good prognosis in all patients(P 1?4.048). It has been an independent factor associated with a good outcome in the IDH mutation(IDH-mut) subgroup(P 1?4.018), but it has also been associated with a poor outcome in the IDH wild-type(IDH-wt) subgroup(P 1?4.049). Combining TERTp-mut and IDH-mut allowed the grade II/III malignancies to be reclassified into IDH-mut/ TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt. 1p/19 q co-deletion, TP53-muts, Ki-67 expression differences, and p-MET expression differences characterized IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt subtypes, respectively. Conclusions Our results showed that TERTp-mut combined with IDH-mut allowed simple classification of grade II/III gliomas for stratifying patients and clarifying diagnostic accuracy by supplementing standard histopathological criteria.Section Two: IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry Background: The relative contribution of isocitrate dehydrogenase mutations(m IDH) and O6-methylguanine-DNA methyltransferase promoter methylation(meth MGMT) as biomarkers in glioblastoma remain poorly understood. Methods: We investigated the association between meth MGMT and m IDH with progression free survival and overall survival in a prospectively collected molecular registry of 274 glioblastoma patients. Results: For glioblastoma patients who underwent Temozolomide and Radiation Therapy, OS and PFS was most favorable for those with tumors harboring both m IDH and meth MGMT(median OS: 35.8 mo, median PFS: 27.5 mo); patients afflicted glioblastomas with either m IDH or meth MGMT exhibited intermediate OS and PFS(m OS: 36 and 17.1 mo; m PFS: 12.2 mo and 9.9 mo, respectively); poorest OS and PFS was observed in wild type IDH1(wt IDH1) glioblastomas that were MGMT promoter unmethylated(m OS: 15 mo, m PFS: 9.7 mo). For patients with wt IDH glioblastomas, TMZ+RT was associated with improved OS and PFS relative to patients treated with RT(OS: 15.4 mo v 9.6 mo, p<0.001; PFS: 9.9 mo v 6.5 mo, p<0.001). While TMZ+RT and RT treated m IDH patients exhibited improved overall survival relative to those with wt IDH, there were no differences between the TMZ+RT or RT group. These results suggest that m IDH1 conferred resistance to TMZ. Supporting this hypothesis, exogenous expression of m IDH1 in independent astrocytoma/glioblastoma lines resulted in a 3-10 fold increase in TMZ resistance after long-term passage. Conclusion: Our study demonstrates IDH mutation and MGMT promoter methylation status independently associate with favorable outcome in TMZ+RT treated glioblastoma patients. However, these biomarkers differentially impact clinical TMZ response. |
PDF Full Text Request