背景:虽然最近的测序研究表明,10%的儿童胶质瘤是由罕见的种系突变引起的,常见变异体的作用尚未确定,迄今为止,尚未发现儿童CNS肿瘤的全基因组显著风险位点.
方法:三项基于人群的全基因组关联研究(GWASs)的荟萃分析,包括4,069名神经胶质瘤儿童和8,778名多个遗传祖先的对照。在单独的病例对照队列中进行复制。进行了数量性状基因座分析和全转录组关联研究,以评估18,628个基因与脑组织表达的可能联系。
结果:CDKN2B-AS1在9p21.3时的常见变异与星形细胞瘤显著相关,儿童神经胶质瘤最常见的亚型(rs573687,p值6.974e-10,OR1.273,CI951.179-1.374)。该关联是由低级星形细胞瘤(p值3.815e-9)驱动的,并且在所有六个遗传祖先中都表现出单向效应。总的来说,对于神经胶质瘤,该关联接近全基因组意义(rs3731239,p值5.411e-8),而对于高级别肿瘤没有观察到显著的关联。预测的脑组织CDKN2B表达降低与星形细胞瘤显著相关(p值8.090e-8)。
结论:在这项基于人群的GWAS荟萃分析中,我们确定并复制9p21.3(CDKN2B-AS1)作为儿童星形细胞瘤的风险位点,从而建立了儿科神经肿瘤学中常见变异倾向的第一个全基因组重要证据。此外,我们通过显示与脑组织CDKN2B表达降低的可能联系,为关联提供了功能基础,并证实了低级和高级星形细胞瘤之间的遗传易感性不同。
Although 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 central nervous system tumors have been identified to date.
Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 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.
Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, P-value of 6.974e-10, OR 1.273, 95% CI 1.179-1.374). The association was driven by low-grade astrocytoma (P-value of 3.815e-9) and exhibited unidirectional effects across all 6 genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, P-value of 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 of 8.090e-8).
In this population-based genome-wide association
study 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.