Clinical impact of combined epigenetic and molecular analysis of pediatric low-grade gliomas

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.

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor

“…Classification of glial and glioneuronal neoplasms is an evolving process that is no longer exclusively based on the combination of radiographic and histologic features, but also now includes both genetic and epigenetic signatures to facilitate the most accurate subtyping and prognostication [7,13,20,29,35]. One challenge that has arisen in terms of CNS tumor classification is that many genetic alterations are not specific to individual tumor entities, but can be seen across a multitude of different tumor types.…”

Radiomics of Pediatric Low-Grade Gliomas: Toward a Pretherapeutic Differentiation of BRAF-Mutated and BRAF-Fused Tumors

“…Although genetic alterations of pLGGs are well-analyzed, 8,20,27 little is known about the correlation between molecular markers and imaging characteristics. While many studies investigated the use of qualitative and quantitative features derived from conventional and advanced sequences to differentiate high-and low-grade pediatric brain tumors, [28][29][30][31][32][33][34][35][36][37][38] only a few studies tried to link imaging characteristics to molecular markers.…”

Advances in the molecular classification of pediatric brain tumors: a guide to the galaxy

“…In addition, some pLGGs have BRAF activating point mutations, such as BRAF V600E [9]. The MAPK and P13K/mTOR pathways may be activated in these tumors as well through intragenetic duplication of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FGFR1) [10][11][12].…”