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Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours
Acta Neuropathologica ( IF 9.3 ) Pub Date : 2017-10-20 , DOI: 10.1007/s00401-017-1773-z
Thomas J. Stone , Angus Keeley , Alex Virasami , William Harkness , Martin Tisdall , Elisa Izquierdo Delgado , Alice Gutteridge , Tony Brooks , Mark Kristiansen , Jane Chalker , Lisa Wilkhu , William Mifsud , John Apps , Maria Thom , Mike Hubank , Tim Forshew , J. Helen Cross , Darren Hargrave , Jonathan Ham , Thomas S. Jacques

Glioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be difficult to diagnose due to a lack of robust diagnostic tools. This is illustrated by marked variability in the reported frequencies across different epilepsy surgical series. To address this, we used DNA methylation arrays and RNA sequencing to assay the methylation and expression profiles within a large cohort of glioneuronal tumours. By adopting a class discovery approach, we were able to identify two distinct groups of glioneuronal tumour, which only partially corresponded to the existing histological classification. Furthermore, by additional molecular analyses, we were able to identify pathogenic mutations in BRAF and FGFR1, specific to each group, in a high proportion of cases. Finally, by interrogating our expression data, we were able to show that each molecular group possessed expression phenotypes suggesting different cellular differentiation: astrocytic in one group and oligodendroglial in the second. Informed by this, we were able to identify CCND1, CSPG4, and PDGFRA as immunohistochemical targets which could distinguish between molecular groups. Our data suggest that the current histological classification of glioneuronal tumours does not adequately represent their underlying biology. Instead, we show that there are two molecular groups within glioneuronal tumours. The first of these displays astrocytic differentiation and is driven by BRAF mutations, while the second displays oligodendroglial differentiation and is driven by FGFR1 mutations.



中文翻译:

癫痫相关的胶质神经胶质瘤的综合分子表征

胶质神经元肿瘤是抗药性癫痫的重要原因。肿瘤亚型通常无法通过组织学特征加以区分,并且由于缺乏可靠的诊断工具而可能难以诊断。在不同的癫痫外科手术系列中,报告频率的明显差异说明了这一点。为了解决这个问题,我们使用DNA甲基化阵列和RNA测序来分析一大批神经胶质神经元肿瘤中的甲基化和表达谱。通过采用分类发现方法,我们能够鉴定出神经胶质神经瘤的两个不同的组,它们仅部分地与现有的组织学分类相对应。此外,通过其他分子分析,我们能够鉴定BRAFFGFR1中的致病性突变,在大多数情况下都是针对每个组的。最后,通过查询我们的表达数据,我们能够证明每个分子组具有表达表型,表明不同的细胞分化:一组是星形胶质细胞,另一组是少突胶质细胞。据此,我们能够鉴定出CCND1,CSPG4和PDGFRA作为可以区分分子组的免疫组织化学靶标。我们的数据表明,神经胶质神经元肿瘤的当前组织学分类不能充分代表其基础生物学。相反,我们表明神经胶质神经元肿瘤内有两个分子基团。这些中的第一个显示出星形细胞分化,并受到BRAF的驱动突变,而第二个则显示少突胶质细胞分化,并受FGFR1突变驱动。

更新日期:2017-10-20
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