HGG-21. DISTRIBUTION AND MUTATIONAL PATTERNS OF TP53 ALTERATIONS ACROSS SUBTYPES OF PEDIATRIC HIGH-GRADE GLIOMAS

Abstract

Abstract Inactivating alterations of tumor suppressor gene TP53 are a hallmark of tumor progression in various cancer entities. Unfortunately, TP53 inactivation has not yet provided an actionable vulnerability. To investigate distribution, mutational pattern and impact of TP53 alterations in pediatric high-grade gliomas (pedHGG), we investigated TP53 alterations in 407 pedHGG by analyzing genomic sequencing and survival data collected through the INFORM and MNP molecular diagnostic pipelines. Nearly half of pedHGG (47%) showed signs of genomic TP53 inactivation. A second hit suggesting complete loss of function was observed in 84% of tumors, with loss of heterozygosity as the most common mechanism (70%). The frequency of TP53 alterations ranged from 97% in H3 G34-mutated tumors, 70% in IDH-mutated tumors and 61% in H3 K27-mutated tumors down to 40% in H3-/IDH-wildtype subtypes and none in infant-type hemispheric gliomas. Alterations in TP53 were associated with significantly shorter mean overall survival of 11 vs. 15 months in patients diagnosed with H3 K27-mutated tumors. Previously described TP53 hotspot mutations, such as amino acid substitutions at position 17, 248, 273, 282 and 342 were also prominent in the studied cohort (NM_000546). Mutations at position 342 were enriched in H3 G34-mutated tumors, with one-third carrying a stopgain mutation at this position rarely seen in other pedHGG. G34-mutated tumors also showed an abundance of nonsense, splicing or frameshift mutations in contrast to the predominance of missense mutations in other subtypes. The functional impact of these differences is currently under investigation. Lastly, we observed potential evidence for a genotype-phenotype link with Li-Fraumeni syndrome (LFS)-associated (constitutional) TP53 mutations in pedHGG, including an absence of the R248 hotspot mutation in 15 LFS-associated tumors.