Genome-wide methylation analysis in long-term survivors of glioblastoma (GBM).

Abstract

2552 Background: Identification of tumor characteristics that may be associated with survival in patients with glioblastoma (GBM) has been largely characterized by IDH mutations and MGMT promoter methylation status. However, these genetic changes and other currently available data are not sufficient to explain the longevity experienced by a subset of long-term survivors (LTS) - patients surviving longer than 3 years past diagnosis. Methods: The study identified GBM patients established and treated at University of Iowa Holden Comprehensive Cancer Center from 2007-2017 whose disease recurred after initial resection. Patients were categorized LTS if they survived > = 3 years beyond initial definitive resection; short-term survivors (STS) if less than 3 years. Pathologic specimens at initial and repeat resection underwent genome wide methylation analysis using the Infinium EPIC microarray system. Data were analyzed to identify genes that exhibited differentially methylated CpG regions. Results: Resection specimens from GBM survivors were compared to those of STS. A total of 29 samples were analyzed and compared (15 LTS and 14 STS samples). Multidimensional scaling plots identified significant differences in genomic constitution between LTS and STS specimens. Granular analysis yielded 89 differentially methylated regions significantly associated with long-term survival (adjusted p < 0.05). PTPRN2 (p = 0.000376), PTPN11 (p = 1.38E-05), and PAX6 (p = 0.000671) were found to exhibit numerous differentially methylated CpG sites between MGMT-methylated vs. unmethylated specimens. Further notable, higher levels of differentially methylated CpG shores and open-seas regions on chromosome 12 were associated with long-term survival (p = 1.89E-08). Conclusions: Our study identified multiple significant epigenetic differences that, functionally or consequentially, may be associated with extended survival in GBM patients. The implication that CpG shores, rather than islands, are associated with long-term survival raises further intriguing questions regarding the depth of epigenetic complexity in this disease. More immediately, the surprising association of multiple protein phosphatases with LTS in our study may hint at the class’ previously unspecified, yet integral, role in delaying disease progression and identify new, novel avenues for therapy.