Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma

Abstract

Objectives To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC). Methods 51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31and CD105. Association between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazards model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation. Results Thirty-one angiogenic-related genes were significantly associated with survival (q ≤ 0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q=0.02; TCGA p= 0.01, HR=0.8), CD44 (q= 0.003; TCGA p=0.05, HR=0.9), EPHB2 (q= 0.01; TCGA p=0.05, HR=1.2), and ERBB2 (q= 0.02; TCGA p= 0.05, HR=1.2). While 5 were associated with outcome in the GSE database: FLT1 (q= 0.03; GSE26712 p=0.01, HR=3.1); PF4 (q= 0.02; GSE26712 p=0.01, HR=3.0), NRP1 (q= 0.02; GSE26712 p < 0.04, HR>1.4), COL4A3 (q= 0.04; GSE26712 p= 0.03, HR=1.3), ANGPTL3 (q= 0.02; GSE14764 p=0.02, HR=1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. Conclusions Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.

Expression of CD31 in Mycosis Fungoides

“…In our study, we observed that the increased CD31 expression positively correlated with nodal involvement. In a variety of solid tumors, as well as hematological malignancies, increased angiogenesis is associated with poor prognosis (27,28). Surprisingly, in our study, despite the significant correlation between CD31 expression and MF progression, we did not observe any impact on survival.…”

Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines

“…Of these, high CD44 was associated with longer survival in the TCGA database. In contrast, high expression of EPHB2 and NRP1 were associated with shorter survival in an external database (76). Microarray analysis of cell lines may potentially identify genes that have prognostic significance for survival.…”

“…We conducted an extreme phenotype study that included women with long survival (>7 years) vs. short survival (<3 years) (76). Thirty-one genes were significantly associated with clinical outcome including several of the genes reported in our current study ( CD44−, EPHB2, HIF1A, NRP1 , and TGFA ).…”

The Roles of ANGPTL Families in Cancer Progression

“…In HCC in vitro cells, ANGPTL3 antisense oligodeoxynucleotides inhibit cell proliferation and invasion [37]. ANGPTL3 mRNA level in high-grade serous ovarian carcinoma is associated with shorter survival [38]. In glioblastoma and breast cancer, ANGPTL3 expression in cancer cells provides a predictive factor [39,40], while high ANG-PTL3 expression in renal cell carcinoma (RCC) upregulates in sorafenib-responsive RCC.…”