Abstract 2103: Distinct methylation patterns correlate with unique clinical and genomic profiles of brainstem gliomas

Abstract

Abstract Gliomas of the brainstem and surrounding regions are devastating brain tumors with the highest mortality rates among all cancers. The locations of tumors make surgical resection difficult due to the risk of perioperative mortality. To understand the genetics and molecular biology of this disease, we performed a comprehensive study, combining epigenetic and genomic analyses with clinical features on 126 brainstem gliomas, including 33 diffuse intrinsic pontine gliomas. Based on DNA methylation data, we identified four distinct clusters named H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. Most of the tumors within H3-Pons and H3-Medulla harbored H3F3A mutations, but tumors in these two clusters use different escaping mechanisms for DNA damage response pathway. Most of the tumors in H3-Pons showed TP53 mutations, while H3-Medulla contain PPM1D mutations. We also analyzed the lengths of telomeres in these tumors by whole genome sequencing data, showing striking difference between clusters, suggesting the mechanisms of telomere maintenance differ between different subtypes of brainstem gliomas. Structural variations and alternative splicing based on RNA sequencing demonstrated possible different transcriptome profiling in methylation clusters, and pathway analysis showed different mechanisms in these samples. Our findings suggest that the integration of DNA methylation data into diagnosis could be utilized to better understand brainstem glioma and better defining the classification, therefore guiding future clinical management of patients. Citation Format: Lee H. Chen, Changcun Pan, Sizhen Wang, Hai Yan, Liwei Zhang. Distinct methylation patterns correlate with unique clinical and genomic profiles of brainstem gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2103.