title: Epigenetic analysis of the Notch superfamily in high-grade serous ovarian cancer.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Justin
authors.initials: J
authors.lastname: Bottsford-Miller
authors.forename: Behrouz
authors.initials: B
authors.lastname: Zand
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Dalton
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: Keith A
authors.initials: KA
authors.lastname: Baggerly
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D057890:Epigenomics / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051880:Receptors, Notch / Q000096:biosynthesis / Q000235:genetics*; D016019:Survival Analysis
chemical_list: C530104:CCND1 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D035683:MicroRNAs; D047495:PPAR gamma; D012333:RNA, Messenger; C493728:RUNX1 protein, human; D051880:Receptors, Notch; D019938:Cyclin D1