DNA methylation heterogeneity attributable to a complex tumor immune microenvironment prompts prognostic risk in glioma

ABSTRACT

Gliomas are malignant tumours of the human nervous system with different World Health Organization (WHO) classifications, glioblastoma (GBM) with higher grade and are more malignant than lower-grade glioma (LGG). To dissect how the DNA methylation heterogeneity in gliomas is influenced by the complex cellular composition of the tumour immune microenvironment, we first compared the DNA methylation profiles of purified human immune cells and bulk glioma tissue, stratifying three tumour immune microenvironmental subtypes for GBM and LGG samples from The Cancer Genome Atlas (TCGA). We found that more intermediate methylation sites were enriched in glioma tumour tissues, and used the Proportion of sites with Intermediate Methylation (PIM) to compare intertumoral DNA methylation heterogeneity. A larger PIM score reflected stronger DNA methylation heterogeneity. Enhanced DNA methylation heterogeneity was associated with stronger immune cell infiltration, better survival rates, and slower tumour progression in glioma patients. We then created a Cell-type-associated DNA Methylation Heterogeneity Contribution (CMHC) score to explore the impact of different immune cell types on heterogeneous CpG site (CpG^ct) in glioma tissues. We identified eight prognosis-related CpG^ct to construct a risk score: the Cell-type-associated DNA Methylation Heterogeneity Risk (CMHR) score. CMHR was positively correlated with cytotoxic T-lymphocyte infiltration (CTL), and showed better predictive performance for IDH status (AUC = 0.96) and glioma histological phenotype (AUC = 0.81). Furthermore, DNA methylation alterations of eight CpG^ct might be related to drug treatments of gliomas. In conclusion, we indicated that DNA methylation heterogeneity is associated with a complex tumour immune microenvironment, glioma phenotype, and patient’s prognosis.

KEYWORDS:

• Glioma
• DNA methylation heterogeneity
• tumor immune microenvironment
• prognosis
• T-lymphocyte infiltration
• clinical drug treatment

Authors’ contributions

Y.S.M. and X.P. designed the study, performed analysis, and wrote the manuscript. J.G., X.X.G., H.J.H., Y.H.H., and C.Y.W. revised the manuscript. H.Z. and W.S.N. supervised research and provided critical advice on the study. All authors approved the final manuscript.

Data availability statement

The datasets analysed during the current study are available in the TCGA database; https://www.cancer.gov/tcga/, GEO repository; https://www.ncbi.nlm.nih.gov/geo/, and Xena browser: https://gdc.xenahubs.net. Accession numbers in GEO have been described in the section ‘Materials and Methods’ and Table S1. And custom analysis scripts are available at https://github.com/ShuangyueMa/DMH_glioma.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15592294.2024.2318506

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [32170674].