The molecular characteristics of spinal cord gliomas with or without H3 K27M mutation

Abstract

Due to the rare incidence of spinal cord astrocytomas, their molecular features remain unclear. Here, we characterized the landscapes of mutations in H3 K27M, isocitrate dehydrogenase 1 (IDH1) R132H, BRAF V600E, and the TERT promoter in 83 diffuse spinal cord astrocytic tumors. Among these samples, thirty-five patients had the H3 K27M mutation; this mutant could be observed in histological grade II (40%), III (40%), and IV (20%) astrocytomas. IDH1 mutations were absent in 58 of 58 cases tested. The BRAF V600E mutation (7/57) was only observed in H3-wildtype astrocytomas, and was associated with a better prognosis in all histological grade II/III astrocytomas. TERT promoter mutations were observed in both H3 K27M-mutant (4/25) and-wildtype (9/33) astrocytomas, and were associated with a poor prognosis in H3-wildtype histological grade II/III astrocytomas. In the 2016 WHO classification of CNS tumors, H3 K27M-mutant diffuse midline gliomas, including spinal cord astrocytomas, are categorized as WHO grade IV. Here, we noticed that the median overall survival of histological grade II/III H3 K27M-mutant cases (n = 28) was significantly longer than that of either the total histological grade IV cases (n = 12) or the H3 K27M-mutant histological grade IV cases (n = 7). We also directly compared H3 K27M-mutant astrocytomas to H3-wildtype astrocytomas of the same histological grade. In histological grade II astrocytomas, compared to H3-wildtype cases (n = 37), H3 K27M-mutant patients (n = 14) had showed a significantly higher Ki-67-positive rate and poorer survival rate. However, no significant differences in these parameters were observed in histological grade III and IV astrocytoma patients. In conclusion, these findings indicate that spinal cord astrocytomas are considerably different from hemispheric and brainstem astrocytomas in terms of their molecular profiles, and that the histological grade cannot be ignored when assessing the prognosis of H3 K27M-mutant spinal cord astrocytomas.

Clinical, radiological and molecular characterization of intramedullary astrocytomas

“…In this cohort, nearly all grade IV IMAs were H3K27M mutants (92%), in line with previous reports, which described a range between 38 and 100% of H3K27M-mutant tumors among HG spinal astrocytomas [1,8,17,25,27,32,35,41,42,44,53]. All of the H3F3A mutations identified in our cohort consisted of the recurrent hotspot p.K27M mutation.…”

“…All of the H3F3A mutations identified in our cohort consisted of the recurrent hotspot p.K27M mutation. We did not find any other mutations in genes encoding histone variants H3.1 or additional H3F3A mutations, in contrast with the recent report by Sloan et al, who reported H3F3A p.G34W in grade II and III spinal cord astrocytomas [43].We did not find TERT promoter mutations among HG IMAs, in contrast with those in the brain, and with two recent studies [1,8]. Alvi et al described distinct prognostic groups of HG IMAs according to the presence of TERT promoter mutations and H3K27M mutations [1].…”

“…IDH mutations are generally rare and mostly non-canonical in midline locations [35]. Previous reports of noncanonical IDH mutations in the spine are scarce and restricted to very few cases [8,9,12,41,54] with Takai et al reporting one case with the same IDH1 p.R132S mutation that we found [47]. While for brain gliomas, IDH mutations are commonly associated with good prognosis, in our cohort of LG IMAs, the EFS of the two IDH-mutated cases was 17 and 14 months while for IDH-wild-type cases, the median EFS was 67 months.…”

Transcriptional Characteristics of IDH-Wild Type Glioma Subgroups Highlight the Biological Processes Underlying Heterogeneity of IDH-Wild Type WHO Grade IV Gliomas

“…To verify the finding in TCGA dataset, we also enrolled 99 IDH-wild type patients in our CGGA database (Hu et al, 2018;Chai et al, 2019c), including 27 diffuse astrocytic gliomas whose TERT promoter status had been tested by pyrosequencing as previously reported (Chai et al, 2020), and we classified these patients into three groups: Group A, diffuse astrocytic glioma without TERT promoter mutant; Group B, diffuse astrocytic gliomas with TERT promoter mutant; and Group C, glioblastoma.…”

“…In addition to histologic features, molecular features, such as IDH and 1p/19q codeletion statues, had also been included in the 2016 WHO classification (Louis et al, 2016). IDH-wild type gliomas, including diffuse astrocytic gliomas (WHO grade II/III) and GBM (WHO grade IV), have a poorer prognosis compared with the same histologic IDH-mutant gliomas (Chai et al, 2020). Recently, growing evidence indicated that some IDH-wild type astrocytic gliomas had similar molecular features and prognosis of IDH-wild type GBM (Yang et al, 2016;Aibaidula et al, 2017;Pekmezci et al, 2017;Wijnenga et al, 2017), suggesting that the specific subgroup of IDH-wild type glioma still needs to be further classified.…”