Elsevier

Gynecologic Oncology

Volume 112, Issue 1, January 2009, Pages 47-54
Gynecologic Oncology

A serum based analysis of ovarian epithelial tumorigenesis

https://doi.org/10.1016/j.ygyno.2008.09.043Get rights and content

Abstract

Objectives

Ovarian epithelial carcinoma can be subdivided into separate histological subtypes including clear cell, endometrioid, mucinous, and serous. These carcinoma subtypes may represent distinctive pathways of tumorigenesis and disease development. This distinction could potentially be reflected in the levels of tumor produced factors that enter into the circulation and serve as biomarkers of malignant growth. Here, we analyze levels of circulating biomarkers from a diverse set of patients diagnosed with ovarian carcinoma to identify biomarker trends and relationships associated with distinct carcinoma histotypes and divergent tumorigenic pathways.

Methods

We utilize multiplexed bead-based immunoassays to measure serum levels of a diverse array of fifty-eight biomarkers from the sera of patients diagnosed with various histological subtypes of ovarian carcinoma and benign lesions. The biomarkers studied include cancer antigens, oncogenes, cytokines, chemokines, receptors, growth and angiogenic factors, proteases, hormones, and apoptosis and adhesion related molecules. Levels of each biomarker are compared statistically across carcinoma subtypes as well as with benign cases.

Results

A total of 21 serum biomarkers differ significantly between patients diagnosed with ovarian carcinomas and benign cases. Nine of these biomarkers are specific for carcinomas identified as clear cell, endometrioid, or mucinous in histology, while two biomarkers are specific for the serous histology. In a direct comparison of the histology groups, ten biomarkers are found to be subtype specific. Identified biomarkers include traditional and emerging tumor markers, cytokines and receptors, hormones, and adhesion- and metastasis-related proteins.

Conclusions

We demonstrate here that the divergent histology-based tumorigenic pathways proposed for ovarian epithelial carcinomas are associated with distinct profiles of circulating biomarkers. Continued investigation into the relationships between these factors should reveal new insights into the complex mechanisms underlying ovarian epithelial tumorigenesis.

Introduction

For women in the United States, ovarian cancer ranks eighth among cancers, excluding skin cancer, in terms of incidence, but moves up to fifth in a ranking of age-adjusted mortality [1]. Ovarian carcinomas, tumors of the surface epithelium, are by far the most common form of ovarian cancer [2]. The notion that ovarian carcinomas arise from the surface epithelium or postovulatory inclusion cysts following chronic exposure to hormones is met with widespread agreement [3], however a growing number of clinicians and researchers are beginning to appreciate a far greater heterogeneity concerning the development of ovarian epithelial carcinoma (OEC). Ovarian carcinomas can be classified into the histological subtypes of serous, clear cell, endometrioid, and mucinous which correspond to the different types of epithelia present in the female reproductive tract [4], [5]. Serous tumors, which carry the poorest prognosis, are the most common form of ovarian carcinoma and make up roughly half of all diagnoses [6]. Serous tumors are histologically similar to cancers of the fallopian tube, and range from cystic papillary tumors to solid masses [6]. Endometrioid tumors, accounting for 15–20% of ovarian carcinomas, are characterized by endometrial-like glandular structures [7]. Mucinous tumors often contain cysts and glands lined by mucin-rich cells and constitute 10% of ovarian carcinomas [8]. Clear cell tumors represent 4–12% of ovarian carcinomas and are comprised of clear and hobnailed cells with an immature glomerular pattern [9].

Within the broad spectrum of disease states represented by OEC, there is accumulating clinical, translational, and genetic evidence for the existence of two distinct classes of carcinogenesis [2]. These classes have been termed type I, tumors comprising low-grade serous, mucinous, endometrioid, malignant Brenner, and clear cell carcinoma, and type II, tumors including high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinoma [2], [10]. Type I tumors typically present as early stage neoplasms that pursue an indolent course which may last more than 20 years [11], [12], [13]. Recent findings have traced the development of type I tumors through a stepwise series of well-described precursor lesions [10]. Benign cystadenomas and adenofibromas are believed to give rise to so-called borderline tumors which in turn develop into the type I tumors described above. In contrast to type I tumors, type II tumors are not associated with any recognizable precursors and apparently develop de novo from the surface epithelium or inclusion cysts of the ovary [14]. Type II carcinomas present as late stage, high grade neoplasms that are clinically aggressive, evolve rapidly and metastasize early, and are associated with a poor prognosis [2], [13]. Type II tumors are relatively chemosensitive in comparison to type I tumors [2].

Mutation screening and gene expression profiling have identified a number of molecular alterations and differences in gene expression that distinguish type I ovarian tumors from type II. These distinctions suggest a difference in prognosis and treatment response between the two groups [15], [16]. Most prominent among observed genetic alterations are mutations in the BRAF and KRAS oncogenes, which occur in 28–35% of type I tumors but are largely nonexistent in type II tumors [17]. Mutations in the tumor suppressor gene PTEN and the CTNNB1 gene, which encode β-catenin, are also more prevalent in type I tumors, particularly endometrioid carcinomas [18], [19], [20]. Mutations in TP53 are common in type II carcinomas but relatively rare in type I tumors [21], [22], [23], [24], [25]. Gene expression profiling and immunohistochemical analyses have identified numerous factors that are overexpressed in type II tumors when compared to type I including AKT2, human leukocyte antigen-G (HLA-G), apolipoprotein E, p53, MIB1, and bcl-2 [26], [27], [28], [29].

Here we present an analysis of a diverse array of biomarkers found in the serum of women diagnosed with ovarian cancer. Biomarker levels are compared among patients grouped according to carcinoma subtype as well as with those presenting with benign disease to identify markers that may contribute to or result from a particular carcinogenic pathway. In this manner, we seek to contribute to the evolving body of evidence related to ovarian epithelial tumorigenesis.

Section snippets

Human serum samples

Serum samples from 157 patients diagnosed with ovarian cancer as well as 130 women with benign ovarian lesions were provided by the Gynecological Oncology Group (GOG) (Cleveland, OH) without individual identification of patients. Procedures for serum collection, processing, and storage have been previously described [30]. Written informed consent was obtained for each subject. The diagnostic breakdown of the study population is presented in Table 1 and represents a diverse spectrum of disease

Analysis of serum biomarker levels across ovarian epithelial carcinoma subtypes

Sera from patients presenting with clear cell, endometrioid, and mucinous carcinomas, hereafter termed (CEM), were considered jointly as this group was presumed to represent type I ovarian carcinomas. Patients diagnosed with serous carcinoma presented with tumors that were almost uniformly high grade. Thus, this group was presumed to represent type II carcinomas and was considered separately. Serum biomarker levels from each of these groups were compared to each other as well as to those from

Discussion

Tumorigenesis is a complicated and multi-faceted process that involves unchecked proliferation, immune evasion, angiogenesis, stroma formation, tumor cell invasion and migration, and implantation and growth within distant tissues. To accomplish each of these feats requires a balanced and precise genetic background and tumor microenvironment, the components of which remain largely unresolved by cancer researchers. Here we attempt to identify circulating factors associated with ovarian epithelial

Conflict of interest statement

The authors declare that there are no conflicts of interest.

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