The integrated genomic and epigenomic landscape of brainstem glioma

Lee H Chen,Jie Yang,Bill H Diplas,Changcun Pan,Yibo Geng,Junting Zhang,Changwu Xu ,Landon J Hansen,Guangyu Li,Yu Wang,Xiaoyue Wang,Xin Chen,Yang Zhang,Wenhao Wu,Zhen Wu,Deling Li,Yadong Wu ,Sizhen Wang,David Ashley ,Matthew S Waitkus,Hai Yan,Roger E Mclendon,Yu Sun,Tao Sun,Chen Xu ,Yiping He,Peng Zhang,Liwei Zhang

doi:10.1038/s41467-020-16682-y

Abstract

Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. We perform a comprehensive study incorporating epigenetic and genomic analyses on a large cohort of brainstem gliomas, including Diffuse Intrinsic Pontine Gliomas. Here we report, from DNA methylation data, distinct clusters termed H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. The majority of tumors within H3-Pons and-H3-Medulla harbors H3F3A mutations but shows distinct methylation patterns that correlate with anatomical localization within the pons or medulla, respectively. Clinical data show significantly different overall survival between these clusters, and pathway analysis demonstrates different oncogenic mechanisms in these samples. Our findings indicate that the integration of genetic and epigenetic data can facilitate better understanding of brainstem gliomagenesis and classification, and guide future studies for the development of novel treatments for this disease.

Highlights

Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies
Among the 38 tumors located in the pons, 33 (86.8%) were diagnosed as diffuse high-grade midline gliomas, NOS, and 5 were focal pontine tumors, most likely pilocytic astrocytomas (13.2%)
To analyze the tumor genomic and epigenomic characteristics of this tumor cohort, we performed methylation microarrays (n = 123) and RNA sequencing (RNAseq) (n = 75) on tumors included in this study, and whole genome (n = 97) and panel sequencing (n = 21) on paired tumors and normal controls

Summary

Introduction

Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. Brainstem gliomas represent a heterogeneous group of tumors that arise from the midbrain, pons, or medulla Among these tumors, pediatric diffuse intrinsic pontine glioma (DIPG), with a median overall survival of 9–12 months[1], has been the main research focus for the past five decades due to the inoperability and resistance to chemotherapy and radiotherapy[2,3,4,5,6]. The molecular characteristics of the nonpediatric brainstem gliomas, such as midbrain and medulla oblongata gliomas, remain poorly characterized Research on these tumors has been challenging due to the relatively low incidence rate and the high risks related to surgical resection resulting in low tissue availability. We present two distinct clusters of H3mutant brainstem gliomas, H3-Pons and H3-Medulla, which despite their similar genetic mutations, differ in location, but in methylation pattern, gene expression, and prognosis

Methods

Results

Conclusion