Exploratory analysis of ERCC2 DNA methylation in survival among pediatric medulloblastoma patients

Abstract

Aim: Medulloblastoma is the most frequent malignant pediatric brain tumor. While survival rates have improved due to multimodal treatment including cisplatin-based chemotherapy, there are few prognostic factors for adverse treatment outcomes. Notably, genes involved in the nucleotide excision repair pathway, including ERCC2, have been implicated in cisplatin sensitivity in other cancers. Therefore, this study evaluated the role of ERCC2 DNA methylation profiles on pediatric medulloblastoma survival.

Methods: The study population included 71 medulloblastoma patients (age <18years at diagnosis) and recruited from Texas Children's Cancer Center between 2004 and 2009. DNA methylation profiles were generated from peripheral blood samples using the Illumina Infinium Human Methylation 450 Beadchip. Sixteen ERCC2-associated CpG sites were evaluated in this analysis. Multivariable regression models were used to determine the adjusted association between DNA methylation and survival. Cox regression and Kaplan-Meier curves were used to compare 5-year overall survival between hyper- and hypo-methylation at each CpG site.

Results: In total, 12.7% (n=9) of the patient population died within five years of diagnosis. In our population, methylation of the cg02257300 probe (Hazard Ratio=9.33; 95% Confidence Interval: 1.17-74.64) was associated with death (log-rank p=0.01). This association remained suggestive after correcting for multiple comparisons (FDR p<0.2). No other ERCC2-associated CpG site was associated with survival in this population of pediatric medulloblastoma patients.

Conclusion: These findings provide the first evidence that DNA methylation within the promoter region of the ERCC2 gene may be associated with survival in pediatric medulloblastoma. If confirmed in future studies, this information may lead to improved risk stratification or promote the development of novel, targeted therapeutics.

Keywords: Medulloblastoma; Methylation; Survival.

Figure 1

Kaplan-Meier 5-year survival curve for hypo- (cg02257300 β <1.76%) and hyper-(cg02257300 β ≥ 1.76%) methylation at cg02257300 among Texas Children’s Hospital medulloblastoma patients (N=71)

Figure 2

Observed ERCC2 mRNA expression for hypomethylation (<sample median, N=10) and hypermethylation (≥ sample median, N=10) at cg02257300 among healthy adults with publically available Gene Expression Omnibus data (GEO accession number: GSE49065)