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Structural variants shape driver combinations and outcomes in pediatric high-grade glioma.

ABSTRACT: We analyzed the contributions of structural variants (SVs) to gliomagenesis across 179 pediatric high-grade gliomas (pHGGs). The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases (RTKs), including an SV amplifying a MYC enhancer in 12% of diffuse midline gliomas (DMG), indicating an underappreciated role for MYC in pHGG. SV signature analysis revealed that tumors with simple signatures were TP53 wild type (TP53^WT) but showed alterations in TP53 pathway members PPM1D and MDM4. Complex signatures were associated with direct aberrations in TP53, CDKN2A and RB1 early in tumor evolution and with later-occurring extrachromosomal amplicons. All pHGGs exhibited at least one simple-SV signature, but complex-SV signatures were primarily restricted to subsets of H3.3^K27M DMGs and hemispheric pHGGs. Importantly, DMGs with complex-SV signatures were associated with shorter overall survival independent of histone mutation and TP53 status. These data provide insight into the impact of SVs on gliomagenesis and the mechanisms that shape them.

SUBMITTER: Dubois FPB

PROVIDER: S-EPMC10365847 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Structural variants shape driver combinations and outcomes in pediatric high-grade glioma.

Dubois Frank P B FPB Shapira Ofer O Greenwald Noah F NF Zack Travis T Wala Jeremiah J Tsai Jessica W JW Crane Alexander A Baguette Audrey A Hadjadj Djihad D Harutyunyan Ashot S AS Kumar Kiran H KH Blattner-Johnson Mirjam M Vogelzang Jayne J Sousa Cecilia C Kang Kyung Shin KS Sinai Claire C Wang Dayle K DK Khadka Prasidda P Lewis Kathleen K Nguyen Lan L Malkin Hayley H Ho Patricia P O'Rourke Ryan R Zhang Shu S Gold Rose R Deng Davy D Serrano Jonathan J Snuderl Matija M Jones Chris C Wright Karen D KD Chi Susan N SN Grill Jacques J Kleinman Claudia L CL Goumnerova Liliana C LC Jabado Nada N Jones David T W DTW Kieran Mark W MW Ligon Keith L KL Beroukhim Rameen R Bandopadhayay Pratiti P

Nature cancer 20220704 8

We analyzed the contributions of structural variants (SVs) to gliomagenesis across 179 pediatric high-grade gliomas (pHGGs). The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases (RTKs), including an SV amplifying a MYC enhancer in 12% of diffuse midline gliomas (DMG), indicating an underappreciated role for MYC in pHGG. SV signature analysis revealed that tumors with simple signatures were TP53 wild type (TP53<sup>WT</sup>) but showed alterations in TP53 pathway members PPM ...[more]

PMID: 35788723

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Project description:Pediatric high-grade glioma (HGG) is a type of malignancy that carries a poor prognosis. The genetic analysis of HGGs has previously identified useful mutations, the targeting of which has improved prognosis. Thus, further research into the more common mutations, such as H3 histone variants (HIST1H3B and H3F3A) and BRAF V600E, may be useful in identifying tumors with different prognoses, as the mutations are considered to drive two distinct oncogenic programs. The present study performed a retrospective analysis of pediatric HGGs. In total, 42 cases of HGG, including 32 cases (76.1%) of anaplastic astrocytoma and 10 cases (23.8%) of glioblastoma multiforme (GBM), were assessed. The median age of the patients was 7 years (range, 0-32 years). Mutations on histone H3, in particular the K27M and G34R mutations in the distinct variants HIST1H3B and H3F3A, in addition to the presence of the BRAF V600E mutation, were analyzed in 24 patients. The H3F3A K27M mutation was identified in 7 patients (29.1%), while the HIST1H3B K27M mutation was only observed in 1 patient with GBM. In addition, 5 patients harbored a BRAF V600E mutation (21%), while the H3F3A G34R mutation was not recorded in any of the patients. The overall survival of the wild-type patients at 20 months was 68% [confidence interval (CI): 38-85%] compared with 28% (CI: 0.4-60%) in patients with the H3F3A K27M mutation. These results suggested that patients with the H3F3A K27M mutation had a worse prognosis compared with wild-type patients (P=0.0045). Moreover, 3/5 patients with the BRAF V600E mutation had HGGs that were derived from a previous low-grade glioma (LGG; P=0.001). In conclusion, these results suggested that histone H3 mutations may help predict the outcome in patients with HGG. In addition, the BRAF V600E mutation was found to be associated with an increased risk of anaplastic progression. The novel data of the present study may help better define the clinical and radiological characteristics of glioma.

Dataset Information

Structural variants shape driver combinations and outcomes in pediatric high-grade glioma.

Publications

Structural variants shape driver combinations and outcomes in pediatric high-grade glioma.

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