DNA Methylation Analysis Identifies Patterns in Progressive Glioma Grades to Predict Patient Survival.

Nicole Salazar,Jingyin Weng

doi:10.3390/ijms22031020

Abstract

DNA methylation is an epigenetic change to the genome that impacts gene activities without modification to the DNA sequence. Alteration in the methylation pattern is a naturally occurring event throughout the human life cycle which may result in the development of diseases such as cancer. In this study, we analyzed methylation data from The Cancer Genome Atlas, under the Lower-Grade Glioma (LGG) and Glioblastoma Multiforme (GBM) projects, to identify methylation markers that exhibit unique changes in DNA methylation pattern along with tumor grade progression, to predict patient survival. We found ten glioma grade-associated Cytosine-phosphate-Guanine (CpG) sites that targeted four genes (SMOC1, KCNA4, SLC25A21, and UPP1) and the methylation pattern is strongly associated with glioma specific molecular alterations, primarily isocitrate dehydrogenase (IDH) mutation and chromosome 1p/19q codeletion. The ten CpG sites collectively distinguished a cohort of diffuse glioma patients with remarkably poor survival probability. Our study highlights genes (KCNA4 and SLC25A21) that were not previously associated with gliomas to have contributed to the poorer patient outcome. These CpG sites can aid glioma tumor progression monitoring and serve as prognostic markers to identify patients diagnosed with less aggressive and malignant gliomas that exhibit similar survival probability to GBM patients.

Highlights

DNA methylation is a heritable epigenetic marker in the genome that does not impact the genetic makeup through the addition of a methyl group to the DNA molecule.Most DNA methylation in humans occur at the 50 carbon of the cytosine base which is followed by a guanine nucleotide
We assessed the correlation of our prognostic markers with the molecular subtypes described by Ceccarelli et al [19] and the methylation pattern of these CpG sites are similar for samples within the same molecular subtype; the CpG sites we identified align with the molecular profile that distinguishes glioma samples into smaller subtypes suggested by Ceccarelli et al The effect of isocitrate dehydrogenase (IDH) and chromosome 1p/19q codeletion alterations on these ten prognostic markers was evaluated and cg16270885 shows a sharp methylation pattern between different IDH and 1p/19q codeletion status
We need improved systematic approaches to monitor tumor progression and predict patient survival based on the real-time molecular changes that result from tumorigenesis and progression

Summary

Introduction

Most DNA methylation in humans occur at the 50 carbon of the cytosine base which is followed by a guanine nucleotide. DNA methylation in the genome exhibits tissue- and cell-type differences, for example, highly methylated content is observed in brain tissue [5]. Other than these differences, which occur naturally during the human life cycle, methylation changes are related to diseased cell states. Hypermethylation involves DNA methylation events at the Cytosine-phosphate-Guanine (CpG) site within the promoter of tumor suppressor gene while hypomethylation removes the methyl group at the promoter site of oncogenes and can be widespread around the genome to promote tumor progression [9,10]

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Results

Conclusion