High frequency of H3F3A K27M mutations characterizes pediatric and adult high-grade gliomas of the spinal cord

Abstract

We identified 16 HGG (11 glioblastomas, 3 anaplastic astrocytomas and 2 anaplastic gangliogliomas, 16/30, 53 %) and 1 diffuse astrocytoma harboring H3F3A K27M mutations ( Fig. 1a-e). The frequency of mutations among HGG affecting adults and children was similar (52 vs. 54 %). The mean age of adult patients with mutated tumors was lower (34 years) than that observed in patients with wild-type tumors (53 years) (Fig. 1f). All tumors affecting infants were H3F3A wild type. The distributions of mutated and wild-type HGG along the spinal cord appeared similar, but in cervical spine HGG were more frequently mutated (Fig. 1g). Neither H3F3A wild-type HGG nor DA showed immunoreactivity for mutant IDH1 R132H protein (not shown).Histones are nuclear proteins which regulate DNA replication and transcription by modifying the nucleosome structure [9]. H3.3 histone proteins, encoded by H3.3A (H3F3A) and H3.3B, are deposited on chromatin in a replication-independent manner and are enriched at actively transcribed genes and heterochromatic regions [9]. H3F3A mutations occur in a hotspot region (K27 and G34) undergoing posttranslational modifications. Similar to IDH1 mutated gliomas in adults, reduced H3.3K27 trimethylation and deregulated DNA methylation are considered to play a major role in pediatric gliomagenesis [2]. Recently, several groups have highlighted the high frequency of H3F3A K27M mutations in pediatric midline HGG as well as in DIPG [2, 3, 7, 8]. These mutations are not limited to pediatric patients, but can occur, although more rarely, in adults. H3F3A K27M mutations were frequently observed in thalamic HGG affecting young adults [1] and adult DIPG, but rare in supratentorial adult HGG [6]. Notably, the patient's age did not affect the pattern of methylation in H3F3A K27M mutant tumors [1].Diffuse high-grade gliomas (HGG) in the spinal cord are rare [5]. It is still undetermined whether they could share genetic alterations with their supratentorial counterparts: in particular, because the spinal cord has to be considered a midline structure, a high incidence of H3F3A K27M mutations could be hypothesized, as reported in diffuse pontine gliomas (DIPG) and in pediatric midline HGG [1-3, 6-8].In this study, we investigated the H3F3A K27M status of 30 primary spinal HGG affecting pediatric and adult patients.Formalin-fixed paraffin-embedded specimens of 36 primary spinal diffusely infiltrating gliomas, including 30 HGG (18 glioblastomas, WHO IV; 10 anaplastic astrocytomas, WHO III; 2 anaplastic gangliogliomas, WHO III) and 6 diffuse astrocytomas (WHO II) [5] were retrieved from the archives

Genetic mutations in high grade gliomas of the adult spinal cord

“…In a previous study, the comprehensive analysis of DNA methylation and gene expression in H3F3A K27 M mutated tumors identified not only a significantly lower expression of FOXG1 but also a significantly higher expression of Olig2 [3]. However, both our cases exhibited overexpression of FOXG1 and Olig2 in a manner Among several studies investigating diffuse astrocytoma, NOS of the spinal cord, only one of nine cases (11 %) exhibited H3F3A K27 M mutation [10]. Although we have no outcome data for spinal diffuse midline glioma, H3 K27 M-mutant, a previous study showed that diffuse midline glioma, H3 K27M mutant in brain stem and thalamus tended to be associated with poorer outcomes [8].…”

The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children

“…The occurrence of H3 K27M mutations has now been expanded to additional midline locations including the third ventricle, hypothalamus, pineal region, and cerebellum [33]. While pontine K27M mutations are found in younger patients, K27M mutations have been increasingly recognized in diffuse midline gliomas of adolescents and adults, occurring in 52–58% of adult spinal cord, brainstem, and thalamic gliomas [34, 35]. Diffuse gliomas with K27M mutations have been reported in the thalamus and spinal cord with a median age of 24 years, and in the pineal region of a 65-year-old patient [33].…”

Molecular Testing of Brain Tumor

“…The circumscribed low-grade gliomas such as pilocytic astrocytoma, pilomyxoid astrocytoma, ganglioglioma, and PXA often harbor the BRAF V600E or FGFR1 mutation, or gene fusions involving BRAF with KIAA1549 or FAM131B [35,62,65]. Histone H3 K27M, K36, and G34 mutations should be studied in pediatric glioma arising in the midline of CNS, i.e., the thalamus, pons, and spinal cord [124]. However, the histone G34 mutation can be present in cerebral high-grade diffuse gliomas of the adult (about 5%) and the histone K36 mutation is rarely found in pediatric midline gliomas [84].…”