Evidence for age-related contributions of DNA damage and epigenetics in brain tumorigenesis.

Abstract

Glioblastoma (GBM) is a highly malignant primary brain tumour displaying rapid cell proliferation and infiltration. GBM primarily occurs at older age; however, younger populations have also been affected. In GBM and other cancers, genetic and epigenetic alterations promote tumorigenesis causing increased cell proliferation and invasiveness. This investigation explored epigenetic events as contributing factors, especially in gliomas that arise in patients aged 40-60years. Furthermore, DNA damage in tumours with respect to age was assessed. Archival fixed tissues from 88 cases of glioblastoma and adjacent non-malignant tissues were tested. Global methylation and DNA damage were measured using ELISA detection of 5-methyl cytosine and 8-hydroxy guanine, respectively. IDH mutations and CDKN2 promoter hypermethylation were analysed by pyrosequencing. Tumour tissue was hypomethylated compared with non-malignant tissue (P=.001), and there was a trend towards increased methylation with increasing age. There was a significant increase in DNA damage in patients older than forty years compared with those aged forty years or younger (P=.035). CDKN2 promoter methylation levels followed the age trends of global methylation in this patient group. Patients younger than 60 had more frequently mutated IDH (P=.004). Conclusions: The data support the potential of epigenetic factors in promoting tumorigenesis in younger patients, while increased DNA damage contributes to tumorigenesis in the older patients.