Epigenetic analysis of the Notch superfamily in high-grade serous ovarian cancer.

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.

[1]  Y. Tsao,et al.  Peroxisome proliferator–activated receptor-γ agonists cause growth arrest and apoptosis in human ovarian carcinoma cell lines , 2006, International Journal of Gynecologic Cancer.

[2]  B. Spiegelman,et al.  Loss-of-function mutations in PPAR gamma associated with human colon cancer. , 1999, Molecular cell.

[3]  B. Spiegelman,et al.  Loss-of-Function Mutations in PPARγ Associated with Human Colon Cancer , 1999 .

[4]  A. Evans,et al.  miRNA profiling in metastatic renal cell carcinoma reveals a tumour-suppressor effect for miR-215 , 2011, British Journal of Cancer.

[5]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[6]  X. Zhong,et al.  Epigenetics of ovarian cancer: from the lab to the clinic. , 2010, Gynecologic oncology.

[7]  A. Ciccodicola,et al.  A Novel Peroxisome Proliferator-activated Receptor γ Isoform with Dominant Negative Activity Generated by Alternative Splicing* , 2005, Journal of Biological Chemistry.

[8]  A. Sood,et al.  Microenvironment and Pathogenesis of Epithelial Ovarian Cancer , 2010, Hormones & cancer.

[9]  D. Ma,et al.  Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cell lines. , 2009, Leukemia research.

[10]  P. V. van Diest,et al.  Epigenetics in ovarian cancer. , 2012, Methods in molecular biology.

[11]  Jianfang Li,et al.  Down‐regulated miR‐625 suppresses invasion and metastasis of gastric cancer by targeting ILK , 2012, FEBS letters.

[12]  D. Heo,et al.  PPARγ ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells. , 2011, Biochemical and biophysical research communications.

[13]  S. Winandy,et al.  Ikaros Regulates Notch Target Gene Expression in Developing Thymocytes1 , 2008, The Journal of Immunology.

[14]  B. Davidson,et al.  Expression of the peroxisome proliferator–activated receptors–α, –β, and –γ in ovarian carcinoma effusions is associated with poor chemoresponse and shorter survival , 2009 .

[15]  R. Ozols,et al.  Reclassification of serous ovarian carcinoma by a 2‐tier system , 2012, Cancer.

[16]  C. Croce,et al.  MicroRNA signatures in human ovarian cancer. , 2007, Cancer research.

[17]  J. Dering,et al.  Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer , 2010, Breast Cancer Research and Treatment.

[18]  Béatrice Desvergne,et al.  Peroxisome-proliferator-activated receptors and cancers: complex stories , 2004, Nature Reviews Cancer.

[19]  X. Yang,et al.  Jagged‐1‐mediated activation of notch signalling induces adipogenesis of adipose‐derived stem cells , 2012, Cell proliferation.

[20]  Shuang-Di Li,et al.  The role of microRNAs in ovarian cancer initiation and progression , 2010, Journal of cellular and molecular medicine.

[21]  Kenneth Shroyer,et al.  Prognostic significance of miR-215 in colon cancer. , 2011, Clinical colorectal cancer.

[22]  Anil K Sood,et al.  Early events in the pathogenesis of epithelial ovarian cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.