Elsevier

Gynecologic Oncology

Volume 96, Issue 2, February 2005, Pages 355-361
Gynecologic Oncology

High insulin-like growth factor-2 (IGF-2) gene expression is an independent predictor of poor survival for patients with advanced stage serous epithelial ovarian cancer

https://doi.org/10.1016/j.ygyno.2004.10.012Get rights and content

Abstract

Objective.

Epithelial ovarian cancer is the deadliest gynecologic malignancy, yet its molecular etiology remains poorly understood. Evidence is accumulating to support a role for the insulin-like growth factor family in human carcinogenesis, and recently using microarray expression analysis, we demonstrated over-expression of the insulin-like growth factor-2 (IGF-2) gene in advanced stage epithelial ovarian cancers. The purpose of the current study is to further elucidate the role of the IGF-2 gene in ovarian cancer development and progression.

Methods.

Relative expression of IGF-2 was measured in 109 epithelial ovarian cancers and eight normal ovarian surface epithelial (NOSE) samples, using quantitative real-time polymerase chain reaction. Associations with clinicopathological parameters were examined.

Results.

Expression of the IGF-2 gene was more than 300-fold higher in ovarian cancers compared with normal ovarian surface epithelium samples (P <0.001). High IGF-2 expression was associated with advanced stage disease at diagnosis (P <0.001), high-grade cancers (P <0.05) and sub-optimal surgical cytoreduction (P = 0.08). In multivariate analysis, relative IGF-2 expression was an independent predictor of poor survival.

Conclusions.

Expression of the IGF-2 gene is significantly higher in ovarian cancers relative to normal ovarian surface epithelium. Further, high IGF-2 gene expression is associated with high grade, advanced stage disease, and is an independent predictor of poor survival in patients with epithelial ovarian cancer. As such, IGF-2 is a molecular marker and potential therapeutic target for the most aggressive epithelial ovarian cancers.

Introduction

Epithelial ovarian cancer is the most lethal gynecologic malignancy. Currently, no effective screening or early detection techniques exist and approximately 80% of ovarian cancers have metastasized extensively throughout the peritoneal cavity at the time of diagnosis. Despite surgical cytoreduction and platinum-based chemotherapy, median survival is approximately 3–5 years; however, a minority of women survive much longer [1]. To date, efforts to fully elucidate the molecular etiology of such survival differences have been unsuccessful [2], [3]. It is likely that the marked clinical differences in ovarian cancer stage at presentation, response to therapy, and ultimately survival are manifestations of a complex underlying molecular heterogeneity, such that traditional single-gene analysis techniques have proven inadequate. The recent development of microarray expression analysis technology has transformed the study of carcinogenesis by enabling the simultaneous study of thousands of genes in a single sample. Study of genome-wide expression is beginning to provide a more global understanding of the complex genetic changes that lead to malignant transformation in a variety of cancers.

Our laboratory recently applied microarray technology to identify patterns of gene expression associated with outcome in women with advanced stage epithelial ovarian cancers. A series of 31 advanced stage serous ovarian cancers from patients who survived less than 2 years and more than 7 years were compared with normal ovarian epithelium. Approximately 7070 genes were evaluated using Affymetrix HumanGeneFL arrays. Hierarchical clustering identified patterns of gene expression that distinguished cancer from normal ovarian epithelium, and several members of the insulin-like growth factor family exhibited differential expression between ovarian cancers and normal ovarian surface epithelium samples. Notably, the IGF-2 gene was 13-fold (P <0.01) more highly expressed in 31 advanced ovarian cancers compared to three normal ovarian surface epithelium samples [4].

Previously, expression of the IGF-2 gene has been associated with development of cancers of the breast, colon, and prostate [5], [6], [7]. Additionally, IGF-2 expression has been shown to be elevated in ovarian cancers versus normal ovarian tissue. Sawiris et al. [8] recently analyzed a large series of microarray data in order to develop a gene chip specific to the study of ovarian cancer. The analysis identified 516 up-regulated genes with the IGF-2 gene being the most highly over-expressed of this group.

In light of this, and our recent array findings in advanced serous ovarian cancers, we sought to more fully elucidate the role of IGF-2 in ovarian carcinogenesis by applying quantitative real time polymerase chain reaction to measure the expression of the IGF-2 gene in a more comprehensive panel of epithelial ovarian cancers.

Section snippets

Study population

One hundred and nine fresh frozen epithelial ovarian cancers and eight primary cultures of normal human ovarian surface epithelium samples were obtained with IRB-approved informed consent from patients treated by the Division of Gynecologic Oncology at Duke University Medical Center. Histopathologic subtypes included 83 serous, three endometrioid, seven mucinous, six clear cell, one undifferentiated, and nine mixed type. Ten of the cancers were early stage (I/II), and 99 advanced stage

Results

Quantitative real-time polymerase chain reaction (QRT-PCR) was used to determine relative expression of the IGF-2 gene in 109 epithelial ovarian cancers and 8 normal ovarian surface epithelial samples. Table 1 depicts the distribution of relative IGF-2 expression in the ovarian tissue samples in relation to the various clinicopathological variables of the study population.

Mean relative IGF-2 gene expression in 109 ovarian cancers was approximately 330-fold higher than in 8 normal ovarian

Discussion

The insulin-like growth factor pathway is a complex system comprised of two growth factors (IGF-1 and IGF-2), two cell surface receptors (IGF-1 R and IGF-2 R), six specific high-affinity binding proteins (IGFBP-1 to IGFBP-6), IGFBP proteases as well as several other IGFBP-interacting molecules, which regulate and potentiate IGF actions.

The IGF ligands, IGF-1 and IGF-2, are single chain molecules of 70 and 67 amino acids, respectively. Both ligands interact with high affinity membrane bound

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