Abstract A055: Integrative epigenomic characterization of MGMT and LINE-1 methylation in diffuse gliomas and colorectal cancer: insights from rare brain tumors
TL;DR
Joint assessment of MGMT and LINE-1 methylation uncovers an aggressive epigenomic subtype of rare brain tumors that phenocopies CRC epigenetic features and suggest conserved epigenomic vulnerabilities exploitable by hypomethylating agents.
Abstract
MGMT promoter methylation predicts benefit from alkylating agents in diffuse gliomas, while LINE-1 retrotransposon methylation indicates global epigenetic dysregulation in colorectal tumors. The interplay between these two markers in rare brain gliomas and their relationship to CRC epigenetic subtypes has not been systematically explored. We performed genome-wide DNA methylation profiling (Illumina EPIC array) on 45 rare diffuse glioma samples (including anaplastic oligodendroglioma, gliosarcoma, and high-grade astrocytoma with piloid features) and 60 molecularly characterized CRC specimens. MGMT methylation status was determined by pyrosequencing, and LINE-1 methylation was quantified at individual CpG sites. Unsupervised clustering and immune cell deconvolution were applied to link methylation patterns to tumor microenvironment features. Rare gliomas displayed a wider range of MGMT methylation than previously appreciated, with 30% exhibiting intermediate methylation levels that could not be confidently classified by standard thresholds. LINE-1 hypomethylation formed a distinct epigenetic cluster that contained both a subset of rare gliomas and all CRC MSI-high cases. This cross-tumor hypomethylation cluster was associated with a CpG island methylator phenotype (CIMP)-like signature, high chromosomal instability, and a lymphocyte-depleted immune microenvironment. In the rare glioma subgroup, LINE-1 hypomethylation independently predicted shorter overall survival (HR 2.8, p=0.006). Joint assessment of MGMT and LINE-1 methylation uncovers an aggressive epigenomic subtype of rare brain tumors that phenocopies CRC epigenetic features. These findings support the incorporation of global methylation markers into future rare glioma classification schemes and suggest conserved epigenomic vulnerabilities exploitable by hypomethylating agents. Jinyu Lu. Integrative epigenomic characterization of MGMT and LINE-1 methylation in diffuse gliomas and colorectal cancer: insights from rare brain tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A055.