Abstract
OBJECTIVES:
Gene
methylation and other epigenetic modifications of gene regulation have
been implicated in the growth of ovarian cancer, but the clinical
significance of such modifications in the Notch pathway in high-grade
serous ovarian cancer (HGS-OvCa) is not well understood. We used The
Cancer Genome Atlas (TCGA) data to study the clinical relevance of
epigenetic modifications of
Notch superfamily genes.
METHODS:
We
analyzed the interaction of DNA methylation and miRNAs with gene
expression data for Notch superfamily members with the Spearman rank
correlation test and explored potential relationships with overall
survival (OS) with the log-rank test. We downloaded clinical data, level
3 gene expression data, and level 3 DNA methylation data for 480
patients with stage II-IV HGS-OvCa from the TCGA data portal. Patients
were randomly divided into training and validation cohorts for survival
analyses. In each set, patients were grouped into percentiles according
to methylation and microRNA (miRNA) or messenger RNA (mRNA) levels. We
used several algorithms to predict miRNA-mRNA interaction.
RESULTS:
There
were significant inverse relationships between methylation status and
mRNA expression for PPARG, CCND1, and RUNX1. For each of these genes,
patients with a lower methylation level and higher expression level had
significantly poorer OS than did patients with a higher methylation
level and lower expression level. We also found a significant inverse
relationship between miRNAs and mRNA expression for CCND1, PPARG, and
RUNX1. By further analyzing the effect of miRNAs on gene expression and
OS, we found that patients with higher levels of CCND1, PPARG, and RUNX1
expression and lower expression levels of their respective miRNAs
(502-5p, 128, and 215/625) had significantly poorer OS.
CONCLUSIONS:
Epigenetic
alterations of multiple Notch target genes and pathway interacting
genes (PPARG, CCND1, and RUNX1) may relate to activation of this pathway
and poor survival of patients with HGS-OvCa.
0 comments :
Post a Comment
Your comments?
Note: Only a member of this blog may post a comment.