Abstract
Pediatric high-grade gliomas (HGG) are rare aggressive tumors that present a prognostic and therapeutic challenge. Diffuse midline glioma, H3K27M–mutant is a new entity introduced to HGG in the latest WHO classification. In this study we evaluated the presence of H3K27M mutation in 105 tumor samples histologically classified into low-grade gliomas (LGG) (n = 45), and HGG (n = 60). Samples were screened for the mutation in histone H3.3 and H3.1 variants to examine its prevalence, prognostic impact, and assess its potential clinical value in limited resource settings. H3K27M mutation was detected in 28 of 105 (26.7%) samples, and its distribution was significantly associated with midline locations (p-value < 0.0001) and HGG (p-value = 0.003). Overall and event- free survival (OS and EFS, respectively) of patients with mutant tumors did not differ significantly, neither according to histologic grade (OS p-value = 0.736, EFS p-value = 0.75) nor across anatomical sites (OS p-value = 0.068, EFS p-value = 0.153). Detection of H3K27M mutation in pediatric gliomas provides more precise risk stratification compared to traditional histopathological techniques. Hence, mutation detection should be pursued in all pediatric gliomas. Meanwhile, focusing on midline LGG can be an alternative in lower-middle-income countries to maximally optimize patients’ treatment options.
Highlights
Central nervous system (CNS) tumors are the most common solid tumors in childhood[1]
HIST1H3B K27M mutant tumors were distributed as midline gliomas (MLG) (n = 4) and non-MLG (n = 1), and all of them were histologically classified as high-grade gliomas (HGG)
Our study confirms the prognostic significance of H3K27M mutation in pediatric gliomas and its strong association with high-grade histology and midline locations
Summary
Central nervous system (CNS) tumors are the most common solid tumors in childhood[1]. Recent studies have reported a high frequency of two point mutations in the genes of the histone variants H3.3 “H3F3A”, and to a lesser extent H3.1 “HIST1H3B”, which results in substitution of lysine amino acid at position 27 with methionine (K27M) or glycine at position 34 with arginine or valine (G34V/R)[9,10]. In its latest version of CNS tumors classification, the World Health Organization (WHO) included a novel entity called “diffuse midline glioma, H3 K27M-mutant” This entity is a lucid illustration of the new principle of “integrated diagnosis” that relies on the combination of the genotypic and phenotypic characteristics of the tumor. We aimed to detect the prevalence of the mutation among each pathological and anatomical subgroup and evaluate its impact on the patients’ survival outcomes
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