Work

Os03.5.a Multi-ancestry Genome-wide Association Study of 4,069 Children With Glioma Identifies 9p21.3 Risk Locus

Year: 2023

Type: conference-abstract

Abstract: BACKGROUND While recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric CNS tumors have been identified to date. MATERIAL AND METHODS Meta-analysis of three population-based genome-wide association studies (GWASs) comprising 4,069 children with glioma and 8,778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18,628 genes. RESULTS Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, p-value 6.974e-10, OR 1.273, CI95 1.179-1.374). The association was driven by low-grade astrocytoma (p-value 3.815e-9) and exhibited unidirectional effects across all six genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, p-value 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (p-value 8.090e-8). CONCLUSION In this population-based GWAS meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/noad137.042

Authors: J Foss-Skiftesvik, S Li, A Rosenbaum, C M Hagen, U K Stoltze, S Ljungqvist, U Hjalmars, K Schmiegelow, L Morimoto, A J De Smith, R Mathiasen, C Metayer, D M Hougaard, B Melin, K M Walsh, J Bybjerg-Grauholm, A M Dahlin, J L Wiemels

Institutions: Copenhagen University Hospital, Rigshospitalet, University of Southern California, Umeå University, Statens Serum Institut, Children's Hospital Los Angeles, University of California, Berkeley

Language: English

Topic: Glioma Diagnosis and Treatment

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

OpenAlex ID: W4386537828

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