TY - JOUR
T1 - Epigenetic analysis of the Notch superfamily in high-grade serous ovarian cancer
AU - Ivan, Cristina
AU - Hu, Wei
AU - Bottsford-Miller, Justin
AU - Zand, Behrouz
AU - Dalton, Heather J.
AU - Liu, Tao
AU - Huang, Jie
AU - Nick, Alpa M.
AU - Lopez-Berestein, Gabriel
AU - Coleman, Robert L.
AU - Baggerly, Keith A.
AU - Sood, Anil K.
N1 - Funding Information:
We thank Elizabeth Hess in the Department of Scientific Publications for helpful editing. This work was supported, in part, by the NIH ( CA 109298 , P50 CA083639 , P50 CA098258 , CA128797 , RC2GM092599 , U54 CA 151668 ), the Ovarian Cancer Research Fund, Inc. (Program Project Development Grant), the DOD ( OC073399 , OC093146 , OC100237 , BC085265 ), CPRIT ( RP110595 ), the Zarrow Foundation , the Marcus Foundation , the RGK Foundation , the Gilder Foundation , and the Betty Anne Asche Murray Distinguished Professorship .
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
KW - Epigenetic alterations
KW - High-grade serous ovarian carcinoma
KW - Notch pathway
UR - http://www.scopus.com/inward/record.url?scp=84873606812&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873606812&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2012.11.029
DO - 10.1016/j.ygyno.2012.11.029
M3 - Article
C2 - 23200915
AN - SCOPUS:84873606812
SN - 0090-8258
VL - 128
SP - 506
EP - 511
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 3
ER -