Hg-95integrated Molecular Meta-analysis of 1000 Paediatric High Grade Glioma and Dipg
Year: 2016
Type: review
Abstract: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are a phenotypically diverse collection of tumours which recent molecular profiling studies have refined into age- and location-based subgroups driven by unique genetic and epigenetic alterations. Despite this, the rarity of these tumours means individual studies are underpowered to investigate subgroup-specific alterations and to identify low frequency events recurrently targeting specific pathways. We have collated genomic data from 254 unpublished cases up to 30yrs along along with those from 15 previously published datasets in an integrated analysis comprising 1099 samples from 1061 unique patients, with histone mutation status available for 883 cases (n = 67 H3.3G34R/V, n = 306 H3.3K27M, n = 59 H3.1/H3.2K27M). The full dataset comprises genomic profiles from DNA copy number arrays (Agilent_44K, n = 109; Affymetrix_500K, n = 81; Affymetrix_SNP6, n = 87; BAC, n = 60), Illumina_450K (n = 424), whole exome (n = 225) and genome (n = 111) sequencing. Excluding hyper-mutated cases linked to germline DNA repair defects, H3.3G34R/V tumours harboured a significantly elevated rate of somatic mutations (27.5 vs 12.0, p = 0.001) and CNAs (15.5 vs 13.0, p = 0.04), alongside co-incident mutations in ATRX and TP53. Aberrations in homologous recombination were also significantly enriched in H3.3K27M cases, focused instead on amplification/mutation in TOP3A, BRCA2, BLM and RAD52. H3.1K27M were highly concordant with ACVR1 mutations, however low frequency mutually exclusive events targeting other elements of the TGFb pathway (CAV1, SOS1, SPTBN1, RHOA) were significantly enriched in histone wild-type cases. These integrated data help to further define the diversity of the disease and provide a basis for a functionally defined future treatment stratification.
Source: Neuro-Oncology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2425645079