Abstract

Background

Both genetic and methylation analysis have been shown to provide insight into the diagnosis and prognosis of many brain tumors. However, the implication of methylation profiling and its interaction with genetic alterations in pediatric low-grade gliomas (PLGGs) are unclear.

Methods

We performed a comprehensive analysis of PLGG with long-term clinical follow-up. In total 152 PLGGs were analyzed from a range of pathological subtypes, including 40 gangliogliomas. Complete molecular analysis was compared with genome-wide methylation data and outcome in all patients. For further analysis of specific PLGG groups, including BRAF p.V600E mutant gliomas, we compiled an additional cohort of clinically and genetically defined tumors from 3 large centers.

Results

Unsupervised hierarchical clustering revealed 5 novel subgroups of PLGG. These were dominated by nonneoplastic factors such as tumor location and lymphocytic infiltration. Midline PLGG clustered together while deep hemispheric lesions differed from lesions in the periphery. Mutations were distributed throughout these location-driven clusters of PLGG. A novel methylation cluster suggesting high lymphocyte infiltration was confirmed pathologically and exhibited worse progression-free survival compared with PLGG harboring similar molecular alterations (P = 0.008; multivariate analysis: P = 0.035). Although the current methylation classifier revealed low confidence in 44% of cases and failed to add information in most PLGG, it was helpful in reclassifying rare cases. The addition of histopathological and molecular information to specific methylation subgroups such as pleomorphic xanthoastrocytoma–like tumors could stratify these tumors into low and high risk (P = 0.0014).

Conclusion

The PLGG methylome is affected by multiple nonneoplastic factors. Combined molecular and pathological analysis is key to provide additional information when methylation classification is used for PLGG in the clinical setting.

中文翻译：

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表观遗传学和分子分析相结合的小儿低度神经胶质瘤的临床影响

摘要

背景

遗传和甲基化分析均已显示出可洞悉许多脑肿瘤的诊断和预后。然而，目前尚不清楚小儿低度神经胶质瘤（PLGGs）中甲基化图谱的含义及其与遗传改变的相互作用。

方法

我们对PLGG进行了综合分析，并进行了长期临床随访。总共对152种PLGG进行了分析，其中包括40种神经节胶质瘤。将所有患者的完整分子分析与全基因组甲基化数据和结果进行比较。为了进一步分析特定的PLGG组，包括BRAF p.V600E突变型神经胶质瘤，我们从3个大型中心收集了另一组临床和遗传定义的肿瘤。

结果

无监督分层聚类揭示了PLGG的5个新的亚组。这些以非肿瘤因素如肿瘤位置和淋巴细胞浸润为主。中线PLGG聚集在一起，而深半球病变与周围病变不同。突变分布在这些位置驱动的PLGG集群中。与具有相似分子改变的PLGG相比，病理证实新的甲基化簇提示高淋巴细胞浸润并显示出较差的无进展生存期（P = 0.008；多因素分析：P= 0.035）。尽管当前的甲基化分类器在44％的病例中显示出低置信度，并且在大多数PLGG中未能添加信息，但它有助于对罕见病例进行重新分类。在特定的甲基化亚组（如多形性黄体星形细胞瘤样肿瘤）中添加组织病理学和分子信息可将这些肿瘤分为低风险和高风险（P = 0.0014）。

结论

PLGG甲基化组受多种非肿瘤因素的影响。当在临床环境中将甲基化分类用于PLGG时，结合分子和病理学分析是提供附加信息的关键。