High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts

Abstract

Background Considering that pediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs). Methods We performed a multicentric retrospective study of 112 AYAs from adult and pediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyze their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25 years, histopathological HGG diagnosis, available clinical data, and preoperative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next-generation sequencing, whole exome sequencing, and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 World Health Organization (WHO) classification. Results Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of pediatric subtypes (histone H3-mutants, 40%) but also adult subtypes (isocitrate dehydrogenase [IDH] mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH mutants, and 1p/19q codeletion and the relative high frequency of “rare adult IDH mutations” (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to what is observed in children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance. Conclusions HGGs in AYAs could benefit from a specific classification, driven by molecular subtyping rather than age group. Collaborative efforts are needed from pediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs. Key Points 1. Pediatric subtypes (H3G34 and H3K27 mutants) were the most common HGGs in AYAs. 2. Contrary to what is observed in children, non-brainstem diffuse midline gliomas are more frequent than diffuse intrinsic pontine gliomas. 3. WHO grade has no prognostic value contrary to molecular subgrouping.

A common classification framework for histone sequence alterations in tumours: an expert consensus proposal

“…In children, diffuse midline gliomas, H3 K27-altered, are preferentially located in the brainstem, particularly in the pons, also known as diffuse intrinsic pontine glioma (DIPG), whereas diffuse midline gliomas, H3 K27-altered, in adults are more commonly seen in the thalamus or spinal cord [40,41]. The vast majority of H3 K27-altered diffuse midline gliomas contain the p.Lys28Met (K27M) missense change in one of the histone H3 isoforms [25,42], while individual cases of DIPG may carry a p.Lys28Ile (K27I) substitution [24].…”

L’art de la guerre appliqué aux DIPG

“…Les oligodendrogliomes, qui se développent à partir des oligodendrocytes, représentent un autre exemple des différences moléculaires entre gliomes pédiatriques et gliomes adultes : la perte des fragments de chromosomes 1p et 19q est en effet très rare dans ces tumeurs chez l'enfant alors qu'elle est caractéristique de la majorité de celles de l'adulte. Il est aussi important de signaler que certaines altérations moléculaires sont associées à des gliomes touchant l'adolescent et le jeune adulte, qui diffèrent à la fois des gliomes de l'enfant et de ceux de l'adulte [11]. En ce qui concerne les DIPG, le séquençage du génome a permis de mettre en évidence de manière frappante des mutations spécifiques touchant des gènes codant des histones, H3F3A et HIST1H3B, codant respectivement les histones H3.3 et H3.1, induisant dans leur extrémité N-terminale (la partie libre de la molécule) un changement du résidu lysine 27 en méthionine (K27M) [12,13].…”

Synchronous supratentorial and infratentorial oligodendrogliomas with incongruous IDH1 mutations, a case report

“…High-grade gliomas in adolescents and young adults (AYA, 15–25 years old) have been recently shown to harbor distinct molecular features compared to both the pediatric and adult population. In this particular age group, WHO grade may have limited utility whereas molecular subtypes have a major prognostic impact [ 19 ]. Interestingly, noncanonical IDH1 mutations have been identified with a higher frequency in AYA gliomas compared to the adult patient population [ 19 ].…”

“…In this particular age group, WHO grade may have limited utility whereas molecular subtypes have a major prognostic impact [ 19 ]. Interestingly, noncanonical IDH1 mutations have been identified with a higher frequency in AYA gliomas compared to the adult patient population [ 19 ]. The role of distinct molecular features in selecting management strategies, however, remains unclear.…”