Abstract
The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients’ treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0351-2) contains supplementary material, which is available to authorized users.
Highlights
Extensive genomic analyses have recently revealed that the biology of brain tumors, patients’ clinical outcomes, is often determined by combinations of specific genetic and/or epigenetic alterations
Astrocytomas and oligodendrogliomas will be diagnosed based on molecular characterization of the IDH and 1p/19q statuses; diffuse astrocytomas are defined by the presence of IDH1/IDH2 mutations without 1p/19q codeletion, whereas the diagnosis of oligodendrogliomas requires the presence of both IDH mutation and 1p/19q codeletion
Molecular classification based on IDH and TERT defines distinct subgroups of adult gliomas in Cohort 1 All 758 tumor samples from Cohort 1 were screened for mutations in IDH1/2 and TERT hotspots and the copy number status of 1p/19q
Summary
Extensive genomic analyses have recently revealed that the biology of brain tumors, patients’ clinical outcomes, is often determined by combinations of specific genetic and/or epigenetic alterations. The latest edition of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System (revised 4th edition) incorporated molecular classification as a part of the integrated diagnosis, adding this to conventional histopathology and WHO grading [19]. Astrocytomas and oligodendrogliomas will be diagnosed based on molecular characterization of the IDH and 1p/19q statuses; diffuse astrocytomas are defined by the presence of IDH1/IDH2 mutations without 1p/19q codeletion, whereas the diagnosis of oligodendrogliomas requires the presence of both IDH mutation and 1p/19q codeletion. It has been suggested that most astrocytomas with wild-type IDH may resolve into other tumor entities, mostly glioblastomas (GBMs) [28]. For better definition of GBMs in IDH-wild-type tumors, further classification of molecular markers is needed
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