Gliomas display distinct sex-based differential methylation patterns based on molecular subtype

Abstract

Background Gliomas are the most common type of primary brain tumor and one of many cancers where males are diagnosed with greater frequency than females. However, little is known about the sex-based molecular differences in glioblastomas (GBMs) or lower grade glioma (non-GBM) subtypes. DNA methylation is an epigenetic mechanism involved in regulating gene transcription. In glioma and other cancers, hypermethylation of specific gene promoters downregulates transcription and may have a profound effect on patient outcome. The purpose of this study was to determine if sex-based methylation differences exist in different glioma subtypes. Methods Molecular and clinical data from glioma patients were obtained from The Cancer Genome Atlas and grouped according to tumor grade and molecular subtype (IDH1/2 mutation and 1p/19q chromosomal deletion). Sex-specific differentially methylated probes (DMPs) were identified in each subtype and further analyzed to determine if they were part of differentially methylated regions (DMRs) or associated with differentially methylated DNA transcription regulatory binding motifs. Results Analysis of methylation data in 4 glioma subtypes revealed unique sets of both sex-specific DMPs and DMRs in each subtype. Motif analysis based on DMP position also identified distinct sex-based sets of DNA-binding motifs that varied according to glioma subtype. Downstream targets of 2 of the GBM-specific transcription binding sites, NFAT5 and KLF6, showed differential gene expression consistent with increased methylation mediating downregulation. Conclusion DNA methylation differences between males and females in 4 glioma molecular subtypes suggest an important, sex-specific role for DNA methylation in epigenetic regulation of gliomagenesis.

Sex-specific aspects of epidemiology, molecular genetics and outcome: primary brain tumours

“…Data for patients with IDH-mutant glioma with 1p19q codeletion were not mature at the time of the analysis. 23 Sex was not identified as a prognostic factor in a multivariate analysis exploring 71 098 meningioma patients in the USA. 39…”

“…Most of the hypermethylated DMP were characteristics of the tumour subtype, and hypermethylation seemed to be associated with a reduction of the expression of promigratory genes in females and was associated with downregulation of proapoptotic genes in males. 23 In a cohort of 114 glioma patients, a concomitant AIB1 and HER2 amplification was claimed to be associated with resistance to radiotherapy and a worse prognosis in women only. 24 Females were found to have a greater proportion of MGMT promoter methylated tumours (56% vs 43%) among 83 male and 57 female glioblastoma patients in an Italian registry.…”

“…A difference in outcome has been substantiated also for female vs males with gliomas receiving comparable treatment defined by extent of resection. 23 33 40 A comprehensive study based on serial MRI proposed that women indeed respond better to temozolomide chemoradiotherapy than men, 20 but these surprising findings require independent validation. An Italian study indicated that the survival advantage of female patients with glioblastoma was restricted to patients with tumours with MGMT promoter methylation; yet, the sample size was small and sex and methylation status were combined as one parameter in the multivariable analysis which may at least be considered unusual.…”

“…Most of the hypermethylated DMP were characteristics of the tumour subtype, and hypermethylation seemed to be associated with a reduction of the expression of promigratory genes in females and was associated with downregulation of proapoptotic genes in males. 23 …”

Sex Disparities in MGMT Promoter Methylation and Survival in Glioblastoma: Further Evidence from Clinical Cohorts

“…Of particular interest in this context are sex-bound disparities in the epigenetic regulation of glioma, and how they impact downstream gene expression. There is accumulating evidence that gliomas display sex-specific methylation patterns [ 10 , 11 ]. MGMT promoter methylation is more commonly found in females with GBM, with a subsequent better outcome after treatment with alkylating agent temozolomide (TMZ) [ 12 , 13 , 14 , 15 ].…”