Glioma Groups Based on 1p/19q,IDH, andTERTPromoter Mutations in Tumors

Abstract

BACKGROUND The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triplepositive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis.

Molecular Genetics of Secondary Glioblastoma

“…Further, patients who harbored tumors with an IDH mutation exhibit distinct disease characteristics relative to patients with a glioma with wild-type (WT) IDH. In 615 WHO grade II/III gliomas, IDH mutations were identified in 79% of the patient tumors (17). In another series of 457 WHO grade II/III gliomas, 80.7% of the patients were found to harbor an IDH mutation (20).…”

“…Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene lead to enhanced telomerase activity, which results in maintenance of telomere length and promotion of cell survival. Interestingly, TERT mutation is shared among both primary and secondary GBMs, potentially rendering this mutation as an early event in the process of tumorigenesis (17). In addition to these mutations, secondary GBM originating from a lower grade astrocytoma will frequently display mutations in the TP53 and ATRX (adult thalassemia mental retardation x-linked) genes, while anaplastic tumors arising from a lower grade oligodendroglioma lineage will have co-deletions of 1p and19q (2,3,18).…”

“…Conversely, it can be argued that all GBMs harboring a WT IDH are biologically primary GBMs: cases of secondary GBM without an IDH mutation likely represent a progression from an undergraded, lower grade, or anaplastic glioma (8). These assumptions are borne out by recent data that show that gliomas lacking mutation in IDH or having chromosomal loss at 1p and 19q cluster by expression analysis and DNA copy-number profiling (21) and portend a severe prognosis (17). With an increased understanding of molecular markers and their incorporation into clinical trials, the disparity between molecular markers and histopathology-based diagnostics methods becomes more evident.…”

Adjuvant Chemotherapy is Indicated in Patients with Lower Grade Glioma

“…Tumour biomarkers including IDH, 1p19q, and MGMT are associated with prognostic advantage and chemosensitivity [6,7]. Lower grade gliomas which are IDH wild-type and without 1p19q co-deletions are considered morphologically and clinically similar to glioblastoma (WHO Grade IV) [6,8].…”

WHO’s arrived in 2016! An updated weather forecast for integrated brain tumor diagnosis

“…In contrast, grading continues to be based on classic histologic criteria, although early data suggest that these may be inadequate for the IDH-mutant tumors, as no survival time differences were recently found between corresponding WHO grade II and III examples [9]. Nevertheless, grade II and III astrocytoma patients do considerably better than those with IDH-mutant glioblastomas, suggesting that grade still plays some role [2], perhaps, with the criteria for anaplasia needing to be reconsidered. In contrast, the adult IDH-wildtype counterparts often behave like glioblastoma [4], even when appearing lower grade histologically, with many cases presumed to represent early or under-sampled IDH-wildtype glioblastoma, especially if appearing anaplastic on histology, the patient is elderly, and/or there is a rim-enhancement pattern on MR imaging.…”