Abstract
Oligodendrogliomas are defined by mutation in isocitrate dehydrogenase (NADP(+)) (IDH)1/2 genes and chromosome 1p/19q codeletion. World Health Organisation diagnosis endorses testing for 1p/19q codeletion to distinguish IDH mutant (Mut) oligodendrogliomas from astrocytomas because these gliomas require different treatments and they have different outcomes. Several methods have been used to identify 1p/19q status; however, these techniques are not routinely available and require substantial infrastructure investment. Two recent studies reported reduced immunostaining for trimethylation at lysine 27 on histone H3 (H3K27me3) in IDH Mut 1p/19q codeleted oligodendroglioma. However, the specificity of H3K27me3 immunostaining in this setting is controversial. Therefore, we developed an easy-to-implement immunohistochemical surrogate for IDH Mut glioma subclassification and evaluated a validated adult glioma cohort. We screened 145 adult glioma cases, consisting of 45 IDH Mut and 1p/19q codeleted oligodendrogliomas, 30 IDH Mut astrocytomas, 16 IDH wild-type (Wt) astrocytomas, and 54 IDH Wt glioblastomas (GBMs). We compared immunostaining with DNA sequencing and fluorescent in situ hybridization analysis and assessed differences in H3K27me3 staining between oligodendroglial and astrocytic lineages and between IDH1-R132H and non-canonical (non-R132H) IDH1/2 Mut oligodendroglioma. A loss of H3K27me3 was observed in 36/40 (90%) of IDH1-R132H Mut oligodendroglioma. In contrast, loss of H3K27me3 was never seen in IDH1-R132L or IDH2-mutated 1p/19q codeleted oligodendrogliomas. IDH Mut astrocytoma, IDH Wt astrocytoma and GBM showed preserved nuclear staining in 87%, 94%, and 91% of cases, respectively. A high recursive partitioning model predicted probability score (0.9835) indicated that the loss of H3K27me3 is frequent to IDH1-R132H Mut oligodendroglioma. Our results demonstrate H3K27me3 immunohistochemical evaluation to be a cost-effective and reliable method for defining 1p/19q codeletion along with IDH1-R132H and ATRX immunostaining, even in the absence of 1p/19q testing.
Highlights
The current World Health Organisation classification for CNS tumors recommends integrated diagnosis based on combined phenotypic and genotypic findings [1] originating from common progenitor cellsHabiba et al acta neuropathol commun (2021) 9:95 harboring Isocitrate Dehydrogenase (NADP(+)) (IDH) mutations, oligodendrogliomas differ from diffuse astrocytomas by combined whole-arm losses of chromosome 1p and 19q (1p/19q codeletion) and frequent Telomerase Reverse Transcriptase (TERT) promoter mutations
Among IDH Mut gliomas, 80% (36/45) of oligodendrogliomas and 13% (4/30) of astrocytomas exhibited a loss of H3K27me3, with a statistically significant association between 1p/19q codeletion and H3K27me3 loss (P ≤ 0.05)
While the loss of nuclear H3K27me3 was predominantly seen in IDH1-R132H Mut oligodendrogliomas, retained nuclear staining was mostly observed in IDH1 Mut astrocytoma regardless of the mutation type
Summary
Habiba et al acta neuropathol commun (2021) 9:95 harboring Isocitrate Dehydrogenase (NADP(+)) (IDH) mutations, oligodendrogliomas differ from diffuse astrocytomas by combined whole-arm losses of chromosome 1p and 19q (1p/19q codeletion) and frequent Telomerase Reverse Transcriptase (TERT) promoter mutations. Subclassification of IDH mutant (Mut) glioma into astrocytomas and oligodendrogliomas requires testing for 1p/19q codeletion. PCR-based loss of heterozygosity analysis, multiplex ligation-dependent probe amplification, and array comparative genomic hybridization can test 1p/19q status with high reliability [9,10,11,12]. These techniques are labor-intensive and require substantial infrastructure investment, making their global application difficult in countries with less developed healthcare systems
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