GENE-06. INTEGRATIVE ANALYSIS OF DNA METHYLATION SUGGESTS DOWN-REGULATION OF ONCOGENIC PATHWAYS AND REDUCED SOMATIC MUTATION RATES IN SURVIVAL OUTLIERS OF GLIOBLASTOMA. (11th November 2019)

• Record Type: Journal Article
• Authors: Kim, Sojin; Dho, Yun-Sik
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 6
• Page Start: vi98
• Page End: vi99
• Publication Date: 2019-11-11
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz175.408
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: The study of survival outliers of glioblastoma (GBM) can provide important clues on gliomagenesis as well as on the ways to alter clinical course on this almost uniformly lethal cancer type. However, there has been little consensus on genetic and epigenetic signatures of the long-term survival outliers of GBM. In this study, we compared the two groups of survival outliers of glioblastoma with IDH wild-type, consisting of the GBM patients who lived longer than 3 years (n=17) and the patients who lived less than 1 year (n=12) in terms of genome-wide DNA methylation profile. Statistical analyses were performed to identify differentially methylated sites between the two groups. Functional implication of long-term survivors of GBM (LTS-GBM)-specific sites were investigated by comprehensive enrichment analyses with genomic and epigenomic features. We found that the genome of LTS-GBM is differentially methylated relative to short-term survivor patients depending on CpG density: hypermethylation near CpG islands (CGIs) and hypomethylation far from CGIs. Interestingly, these two patterns are associated with distinct oncogenic aspects in gliomagenesis. In the LTS-GBM-specific sites distant from CGI, somatic mutations of GBM are enriched with higher DNA methylation, suggesting that the hypomethylation in LTS-GBM can contribute to reduce the rate of somatic mutation. On the other hand, the hypermethylation near CGIs associates with transcriptional downregulation of genes involved in cancer progression pathways. Using independent cohorts of IDH1/2- wild type GBM, we also showed that these two patterns of DNA methylation can be used as molecular markers of LTS-GBM. Our results provide extended understanding of DNA methylation, especially of DNA hypomethylation, in cancer genome and reveal clinical importance of DNA methylation pattern as prognostic markers of GBM.