A serum based analysis of 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.
References (53)
- et al.
Diverse tumorigenic pathways in ovarian serous carcinoma
Am. J. Pathol.
(2002) - et al.
Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis
Am. J. Obstet. Gynecol.
(2008) Eychene A: the Raf/MEK/ERK pathway: new concepts of activation
Biol. Cell
(2001)- et al.
KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants
Gynecol. Oncol.
(2006) - et al.
Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers
Am. J. Pathol.
(2000) - et al.
Human ovarian cancer of the surface epithelium
Biochem. Pharmacol.
(1997) - et al.
Analysis of host versus tumor interaction in cancer patients: opposing role of transforming growth factor-beta1 and interleukin-6 in the development of in situ tumor immunity
Immunobiology
(2005) - et al.
The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass
Gynecol. Oncol.
(2008) - et al.
Monitoring gene expression profile changes in ovarian carcinomas using cDNA microarray
Gene
(1999) - ...
Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis
Am. J. Pathol.
Ovarian surface epithelium: biology, endocrinology, and pathology
Endocr. Rev.
World health organization international classification of tumours
The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin
Int. J. Gynecol. Pathol.
Differential diagnosis of ovarian tumors based primarily on their patterns and cell types
Semin. Diagn. Pathol.
Histological classification of ovarian cancer
Med. Electron. Microsc.
Ovarian clear cell adenocarcinoma: a continuing enigma
J. Clin. Pathol.
Subclassification of serous borderline tumors of the ovary into benign and malignant types. A clinicopathologic study of 65 advanced stage cases
Am. J. Surg. Pathol.
Noninvasive and invasive micropapillary (low-grade) serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases
Am. J. Surg. Pathol.
Early de novo ovarian carcinoma. A study of fourteen cases
Cancer
Subclassification of ovarian surface epithelial tumors based on correlation of histologic and molecular pathologic data
Int. J. Gynecol. Pathol.
Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma
J. Natl. Cancer Inst.
Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors
Cancer Res.
Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas
Cancer Res.
Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer
J. Natl. Cancer Inst.
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