Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in oligodendroglial tumors

Abstract

Aberrant methylation has been associated with transcriptional inactivation of tumor-related genes in a wide spectrum of human neoplasms. The influence of DNA methylation in oligodendroglial tumors is not fully understood. Genomic DNA was isolated from 61 oligodendroglial tumors for analysis of methylation using methylation-specific multiplex ligation-dependent probe amplification assay (MS-MLPA). We correlated methylation status with clinicopathological findings and outcome. The genes found to be most frequently methylated in oligodendroglial tumors were RASSF1A (80.3%), CASP8 (70.5%), and CDKN2A (52.5%). Kaplan-Meier survival curve analysis demonstrated longer duration of progression-free survival in patients with 19q loss, aged less than 38 years, and with a proliferative index of less than 5%. Methylation of the ESR1 promoter is significantly associated with shorter duration of overall survival and progression-free survival, and that methylation of IGSF4 and RASSF1A is significantly associated with shorter duration of progression-free survival. However, none of the methylation status of ESR1, IGSF4, and RASSF1A was of prognostic value for survival in a multivariate Cox model. A number of novel and interesting epigenetic alterations were identified in this study. The findings highlight the importance of methylation profiles in oligodendroglial tumors and their possible involvement in tumorigenesis.

Keywords: ESR1; IGSF4; methylation; multiplex ligation-dependent probe amplification assay; oligodendroglioma.

Figure 1

Kaplan–Meier curve survival analysis indicating that progression‐free survival was significantly longer with (A) 19q loss (log rank, P = 0.049), (B) age less than 38 years (log rank, P = 0.037), and (C) proliferative index of less than 5% (log rank, P = 0.003).

Figure 2

Kaplan–Meier curve survival analysis indicating that overall survival was significantly longer with (A) age less than 38 years (log rank, P = 0.007) and (B) proliferative index of less than 5% (log rank, P = 0.006).

Figure 3

Kaplan–Meier curve survival analysis indicating that tumors methylated for ESR1 showed poor overall survival than those unmethylated for this gene (log rank, P = 0.013).

Figure 4

Kaplan–Meier curve survival analysis indicating that (A) tumors methylated for ESR1 showed poor progression‐free survival than those unmethylated for this gene (log rank, P = 0.007), (B) tumors methylated for IGSF4 showed poor progression‐free survival than those unmethylated for this gene (log rank, P = 0.003), (C) tumors methylated for RASSF1A showed poor progression‐free survival than those unmethylated for this gene (log rank, P = 0.039).