Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities

Abstract

IDH wild type (IDHwt) anaplastic astrocytomas WHO grade III (AA III) are associated with poor outcome. To address the possibilities of molecular subsets among astrocytoma or of diagnostic reclassification, we analyzed a series of 160 adult IDHwt tumors comprising 120 AA III and 40 diffuse astrocytomas WHO grade II (A II) for molecular hallmark alterations and established methylation and copy number profiles. Based on molecular profiles and hallmark alterations the tumors could be grouped into four major sets. 124/160 (78 %) tumors were diagnosed as the molecular equivalent of conventional glioblastoma (GBM), and 15/160 (9 %) as GBM-H3F3A mutated (GBM-H3). 13/160 (8 %) exhibited a distinct methylation profile that was most similar to GBM-H3-K27, however, lacked the H3F3A mutation. This group was enriched for tumors of infratentorial and midline localization and showed a trend towards a more favorable prognosis. All but one of the 120 IDHwt AA III could be assigned to these three groups. 7 tumors recruited from the 40 A II, comprised a variety of molecular signatures and all but one were reclassified into distinct WHO entities of lower grades. Interestingly, TERT mutations were exclusively restricted to the molecular GBM (78 %) and associated with poor clinical outcome. However, the GBM-H3 group lacking TERT mutations appeared to fare even worse. Our data demonstrate that most of the tumors diagnosed as IDHwt astrocytomas can be allocated to other tumor entities on a molecular basis. exhibited a distinct methylation profile that was most similar to GBM-H3-K27, however, lacked the H3F3A mutation. This group was enriched for tumors of infratentorial and midline localization and showed a trend towards a more favorable prognosis. All but one of the 120 IDHwt AA III could be assigned to these three groups. 7 tumors recruited from the 40 A II, comprised a variety of molecular signatures and all but one were reclassified into distinct WHO entities of lower grades. Interestingly, TERT mutations were exclusively restricted to the molecular GBM (78%) and associated with poor clinical outcome. However, the GBM-H3 group lacking TERT mutations appeared to fare even worse.Our data demonstrate that most of the tumors diagnosed as IDHwt astrocytomas can be allocated to other tumor entities on a molecular basis. The diagnosis of IDHwt diffuse astrocytoma or anaplastic astrocytoma should be used with caution.

Gliomatosis cerebri: no evidence for a separate brain tumor entity

“…In this GC cohort, 10 of 25 tumors were classified as glioblastoma WHO grade IV by histological analysis while DNA methylation profiling revealed IDH wildtype glioblastoma-associated DNA methylation signatures in 12/23 evaluable tumors. Thus, similar to data recently reported for diffuse and anaplastic astrocytic gliomas [3,16,20,23], 450k beadchip-based DNA methylation profiling may lead to a refined diagnosis of GC tumors. This appears to be both biologically and clinically meaningful, since methylation profiling but not focal histology allowed for the identification of a subgroup of GC with poor prognosis.…”

“…Large-scale DNA methylation profiling using Infinium ® HumanMethylation450 beadchip arrays has proven very useful for the elucidation of biologically distinct subgroups of medulloblastoma [10], ependymoma [15], glioblastoma [2,12,19], as well as diffuse and anaplastic gliomas [16,17,23]. In the present study of GC patients, 450k analyses revealed that DNA methylation profiles corresponded to those of several previously defined molecular subgroups of gliomas.…”

Epidemiology and Outcome of Glioblastoma

“…Neural subtype is the most similar to the astrocytic and oligodendrocytic markers. Finally, a group with only telomerase reverse transcripts (TERT) mutation is found in primarily grade IV gliomas (45). According to the 2016 WHO classification of CNS tumors, GBM is divided into the following groups:…”

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017

“…7,11,13,34,35 Analyses of large molecular databases have also suggested a number of other molecular markers as being potential characteristic/prognostic features of specific molecular subgroups. 7,9,11,28,35,37,40 Molecular features suggested by more than one study as markers for subtyping grade II/III gliomas include (1) mutations in the TERT promoter, NOTCH1, CIC, FUBP1, PIK3CA; (2) mutation in or overexpression of TP53; (3) PTEN loss or promoter methylation; (4) loss/deletion of ATRX and CDKN2A/B; (5) amplification of EGFR; and (6) chromosome 7 gain, chromosome 10 loss. 5,9,27,28,[34][35][36][37]40 Due to variability in results across studies, these molecular markers are not currently widely accepted as useful for classifying gliomas.…”