Characterizing temporal genomic heterogeneity in pediatric high-grade gliomas

Abstract

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 of targeted therapy, especially at progression, is increasingly practiced despite a paucity of data regarding temporal and therapy-driven genomic evolution in pHGGs. To study the genetic landscape of pHGGs at recurrence, we performed whole exome and methylation analyses on matched primary and recurrent pHGGs from 16 patients. Tumor mutational profiles identified three distinct subgroups. Group 1 (n = 7) harbored known hotspot mutations in Histone 3 (H3) (K27M or G34V) or IDH1 (H3/IDH1 mutants) and co-occurring TP53 or ACVR1 mutations in tumor pairs across the disease course. Group 2 (n = 7), H3/IDH1 wildtype tumor pairs, harbored novel mutations in chromatin modifiers (ZMYND11, EP300 n = 2), all associated with TP53 alterations, or had BRAF V600E mutations (n = 2) conserved across tumor pairs. Group 3 included 2 tumors with NF1 germline mutations. Pairs from primary and relapsed pHGG samples clustered within the same DNA methylation subgroup. ATRX mutations were clonal and retained in H3G34V and H3/IDH1 wildtype tumors, while different genetic alterations in this gene were observed at diagnosis and recurrence in IDH1 mutant tumors. Mutations in putative drug targets (EGFR, ERBB2, PDGFRA, PI3K) were not always shared between primary and recurrence samples, indicating evolution during progression. Our findings indicate that specific key driver mutations in pHGGs are conserved at recurrence and are prime targets for therapeutic development and clinical trials (e.g. H3 post-translational modifications, IDH1, BRAF V600E). Other actionable mutations are acquired or lost, indicating that re-biopsy at recurrence will provide better guidance for effective targeted therapy of pHGGs.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0479-8) contains supplementary material, which is available to authorized users.

Intratumoral Genetic and Functional Heterogeneity in Pediatric Glioblastoma

“…However, the overall number of somatic nsSNVs was lower in the second sample (69 SNVs) than in the diagnostic sample (109 SNVs), whereas this treatment is known to increase mutational burden in adults. This difference in response to chemotherapy and radiation between pGBM and adult GBM was also noted in an independent cohort of patients in a recent publication (12). Samples 1 and 2 from patient 3 only shared a mutation in PCNX (Fig.…”

“…These findings have contributed to the view that pGBM might have a relatively low level of intratumoral complexity at the genomic and functional levels. However, a recent report identified differences in mutational signatures between matched primary and recurrent pGBM samples using exome sequencing (12).…”

“…It is currently believed that pGBM, similarly to other pediatric cancers, is characterized by relatively bland genomes (11). Furthermore, H3F3A mutations were shown to be clonal in pGBM (12) and to result in global loss of trimethylation of lysine 27 of histone 3 (H3K27me3) in virtually all cells in a tumor (6). These findings have contributed to the view that pGBM might have a relatively low level of intratumoral complexity at the genomic and functional levels.…”

Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

“…More recently, systematic characterization of pHGG PDX models from both early biopsies as well as autopsy tissue has been pursued and biobanks have been established [ 38 , 39 , 40 ]. Comparison of these models may help elucidate and distinguish tumorigenic mechanisms present at diagnosis as opposed to at terminal disease, complementing tumor evolution studies done on primary human tumors [ 14 , 46 ].…”

A Complex Systems Analysis of Cancer Networks

“…PI3K/mTOR (mammalian Target of Rapamycin) and MEK/ERK pathways were shown to be critical to the self-renewal of glioma stem cells (GSC) and mediate cancer stemness in brain tumors (Sunayama et al 2010 [31]). Regardless of the divergent clonal evolution of such tumors, key driver mutations in histone H3 post-translational modifications and IDH1/2 (isocitrate dehydrogenase) were tractable patterns of epigenetic reprogramming in GBM stem cells (Suvà et al, 2014 [30]; Salloum et al, 2017 [32]). Progression to higher grade glioma displayed an overall decrease in methylation, and hypermethylation of a small subset of CpG islands associated with developmental regulators, including FOX, SOX and TBX family genes.…”