Characterizing temporal genomic heterogeneity in pediatric high-grade gliomas

摘要: Pediatric high-grade gliomas (pHGGs) are aggressive neoplasms representing approximately 20% of brain tumors in children. Current therapies offer limited disease control, and patients have a poor prognosis. Empiric use targeted therapy, especially at progression, is increasingly practiced despite paucity data regarding temporal therapy-driven genomic evolution pHGGs. To study the genetic landscape pHGGs recurrence, we performed whole exome methylation analyses on matched primary recurrent from 16 patients. Tumor mutational profiles identified three distinct subgroups. Group 1 (n = 7) harbored known hotspot mutations Histone 3 (H3) (K27M or G34V) IDH1 (H3/IDH1 mutants) co-occurring TP53 ACVR1 tumor pairs across course. 2 (n = 7), H3/IDH1 wildtype pairs, novel chromatin modifiers (ZMYND11, EP300 n = 2), all associated with alterations, had BRAF V600E (n = 2) conserved pairs. included NF1 germline mutations. Pairs relapsed pHGG samples clustered within same DNA subgroup. ATRX were clonal retained H3G34V tumors, while different alterations this gene observed diagnosis recurrence mutant tumors. Mutations putative drug targets (EGFR, ERBB2, PDGFRA, PI3K) not always shared between samples, indicating during progression. Our findings indicate that specific key driver prime for therapeutic development clinical trials (e.g. H3 post-translational modifications, IDH1, V600E). Other actionable acquired lost, re-biopsy will provide better guidance effective therapy