Gliomas in children and adolescents: investigation of molecular alterations with a potential prognostic and therapeutic impact

Abstract

Purpose: Gliomas represent the most frequent central nervous system (CNS) tumors in children and adolescents. However, therapeutic strategies for these patients, based on tumor molecular profile, are still limited compared to the wide range of treatment options for the adult population. We investigated molecular alterations, with a potential prognostic marker and therapeutic target in gliomas of childhood and adolescence using the next-generation sequencing (NGS) strategy.

Methods: We selected 95 samples with initial diagnosis of glioma from patients treated at Pediatric Oncology Institute-GRAACC/UNIFESP. All samples were categorized according to the 2021 World Health Organization Classification of Tumors of the CNS, which included 39 low-grade gliomas (LGGs) and 56 high-grade gliomas (HGGs). Four HGG samples were classified as congenital glioblastoma (cGBM). NGS was performed to identify somatic genetic variants in tumor samples using the Oncomine Childhood Cancer Research Assay^® (OCCRA^®) panel, from Thermo Fisher Scientific^®.

Results: Genetic variants were identified in 76 of 95 (80%) tumors. In HGGs, the most common molecular alteration detected was H3F3A c.83A > T variant (H3.3 K27M) and co-occurring mutations in ATRX, TP53, PDGFRA, MET, and MYC genes were also frequently observed. One HGG sample was reclassified as supratentorial ependymoma ZFTA-fusion positive after NGS was performed. In LGGs, four KIAA1549-BRAF fusion transcripts were detected and this alteration was the most recurrent genetic event and favorable prognostic factor identified. Additionally, genetic variants in ALK and NTRK genes, which provide potential targets for therapy with Food and Drug Administration-approved drugs, were identified in two different cases of cGBM that were classified as infant-type hemispheric glioma, a newly recognized subgroup of pediatric HGG.

Conclusion: Molecular profiling by the OCCRA^® panel comprehensively addressed the most relevant genetic variants in gliomas of childhood and adolescence, as these tumors have specific patterns of molecular alterations, outcomes, and effectiveness to therapies.

Keywords: Central nervous system tumor; Congenital glioblastoma; Gliomas; Molecular profiling; Next-generation sequency; Pediatric brain tumor.

Fig. 1

Genetic alterations identified in tumor samples. a Frequency of mutations by gene in the 95 samples. b Number of variants located on each chromosome. c Number of variants according to class and functional effect. d Number of variants according to clinical significance

Fig. 2

Clinical and molecular profile of gliomas. a Genomic landscape of 39 LGG samples. b Genomic landscape of 56 HGG samples. Left pane indicates the altered gene across all the samples and each vertical bar represents an individual case. The presence of more than one variant in the same gene is represented by multicolored boxes

Fig. 3

Subgroup of HGG in children and adolescents with histone H3.3 alterations  a Clinical and molecular profile of HGG patients with H3.3 K27M or G34R mutation and concomitant variants involving TP53, ATRX, PDGFRA, MET, and MYC genes. b Number of samples with H3.3 K27M or G34R mutation, according to tumor location. c Patients with H3.3 K27-altered tumors showed a worse 5-year overall survival when compared to the wildtype subgroup (χ² = 11.99, p = 0.0005). mut mutation, amp amplification

Fig. 4

Overall survival curves comparisons. a HGG patients showed a worse 10-year overall survival when compared to LGG patients (χ² = 34.59, p < 0.0001). b HGG patients diagnosed under 5 years old (infant) had a better 10-year overall survival when compared to older patients with HGG (χ² = 4.57, p = 0.0324)