Genetic Analysis of the Early Natural History of Epithelial Ovarian Carcinoma

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
PLoS ONE (Impact Factor: 3.23). 04/2010; 5(4):e10358. DOI: 10.1371/journal.pone.0010358
Source: PubMed


The high mortality rate associated with epithelial ovarian carcinoma (EOC) reflects diagnosis commonly at an advanced stage, but improved early detection is hindered by uncertainty as to the histologic origin and early natural history of this malignancy.
Here we report combined molecular genetic and morphologic analyses of normal human ovarian tissues and early stage cancers, from both BRCA mutation carriers and the general population, indicating that EOCs frequently arise from dysplastic precursor lesions within epithelial inclusion cysts. In pathologically normal ovaries, molecular evidence of oncogenic stress was observed specifically within epithelial inclusion cysts. To further explore potential very early events in ovarian tumorigenesis, ovarian tissues from women not known to be at high risk for ovarian cancer were subjected to laser catapult microdissection and gene expression profiling. These studies revealed a quasi-neoplastic expression signature in benign ovarian cystic inclusion epithelium compared to surface epithelium, specifically with respect to genes affecting signal transduction, cell cycle control, and mitotic spindle formation. Consistent with this gene expression profile, a significantly higher cell proliferation index (increased cell proliferation and decreased apoptosis) was observed in histopathologically normal ovarian cystic compared to surface epithelium. Furthermore, aneuploidy was frequently identified in normal ovarian cystic epithelium but not in surface epithelium.
Together, these data indicate that EOC frequently arises in ovarian cystic inclusions, is preceded by an identifiable dysplastic precursor lesion, and that increased cell proliferation, decreased apoptosis, and aneuploidy are likely to represent very early aberrations in ovarian tumorigenesis.

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    • "Alternatively, epithelial cells from the Fallopian tubes may originate inclusion cysts after being implanted into the ovary, as suggested by the occasional presence of ciliated and secretory cells in cortical cyst [7]. The importance of surface epithelium and epithelial inclusion cysts arises from studies demonstrating that these structures eventually presented dysplastic precursor lesions and are susceptible to develop epithelial ovarian cancer [8,9]. "
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    ABSTRACT: The importance of surface epithelium and epithelial inclusion cysts in the ovary arises from studies demonstrating that these structures are susceptible to epithelial ovarian cancer development. The expression of estrogen receptor alpha (ER alpha), androgen receptor (AR), in epithelial cells of the ovary from premenopausal and postmenopausal women is interesting because sexual steroid hormones are involved in cell growth and differentiation. The presence of ER alpha, AR, and the orphan G protein-coupled receptor 30 (GPR30) was demonstrated by immunofluorescence in ovaries obtained from 79 pre and postmenopausal patients, undergoing histero-salpingo-oophorectomy for proliferative gynecological diseases. The proportion of patients that displayed positive reaction for estrogen and androgen receptors in epithelial cells of the ovary was evaluated according to menopausal status and associated pathology. The proportion of patients that displayed a positive receptor expression in the epithelial cells of the ovarian surface and cortical inclusion cysts shows that ER alpha is present in 20 of 79 patients (0.25), AR in 33 of 79 (0.42) and GPR30 in 38 of 55 (0.69). There are no differences in ER alpha, AR, and GPR30 expression between pre and postmenopausal patients and considering the associated pathology, proportions for ER alpha and GPR30 are similar. The patients with cervical cancer show a higher proportion of AR expression in epithelial cells of the ovary, which is statistically significant (P < 0.01) compared with patients with other proliferative diseases. The presence of ER alpha, AR, and GPR30 in the surface epithelial ovarian cells and its derivatives are observed with a proportion that is specific for each receptor. The proportion of expression for these receptors in the epithelial cells of the ovary does not change after menopause. The proportion of ovaries with AR positive epithelial cells in patients with cervical squamous carcinoma is higher compared with other gynecological pathologies.
    Full-text · Article · Nov 2013 · Journal of Ovarian Research
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    • "The concept of OSE as stem cells is in keeping with other stem cell-like characteristics [14] [15], and with the ability of OSE to differentiate structurally and functionally to a fibroblastic phenotype in response to microenvironmental changes and growth factors [4] [16]. In OSE-lined inclusion cysts, serous metaplasia of the flat-to-cuboidal mesothelial OSE to columnar epithelium resembling fimbrial epithelium occurs not only morphologically (Fig. 1) [17] [18] [19] but also functionally, as shown by the immunohistochemical demonstration of the tubal epithelial differentiation markers E-cadherin, Epcam, cilia, and oviduct-specific glycoprotein (OVGP1) in columnar cells adjacent to flat OSE cells within the same inclusion cysts (Fig. 2) [20]. Such gradual transitions from flat mesothelial cells to columnar fimbria-like cells within epithelial inclusion cysts and on the ovarian surface [21] exclude the likelihood that the columnar cells are 'implants' of normal fimbrial epithelium. "
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    ABSTRACT: Objectives: There has been increasing evidence that high grade serous ovarian carcinomas (HGSOCs), the most common and most lethal of all ovarian cancers, originate in oviductal fimbriae and metastasize to the ovary. The alternate hypothesis, that ovarian carcinomas may originate within the ovarian stroma in inclusion cysts lined by ovarian surface epithelium (OSE), has been criticized and often dismissed on the basis of the OSE's embryonic origin, mesothelial phenotype, tissue-specific markers, questionable ability to undergo metaplasia, and the lack of identifiable precursor lesions. This review analyzes these criticisms and summarizes evidence indicating that OSE as a source of ovarian cancers cannot be ruled out. Methods: The literature was reviewed and representative reports were chosen to evaluate the current criticisms of, and evidence in favor of, the OSE hypothesis. Results: The close developmental relationship between the oviduct and OSE, both of which originate in the mesothelial coelomic epithelium, accounts for their capacity to produce similar tumors. Histopathologic and experimental data show that OSE does undergo serous metaplasia, and that transformation of pure OSE cultures produces aggressive neoplasms resembling high- and low-grade serous carcinomas, but never mesotheliomas. There is evidence of premalignant changes (e.g. p53 inactivation) in morphologically normal OSE and of rare but definitive dysplastic and early preinvasive lesions in OSE-lined inclusion cysts. Conclusions based on tissue-specific markers to identify origins of inclusion cysts usually disregard the changes in differentiation occurring when OSE is displaced to the stroma. Lastly, an explanation is offered for the rare detection of precursor lesions in OSE-lined cysts, based on the likelihood that the duration from initiation of malignant transformation to invasive growth is minimal and thus difficult to detect. Conclusion: The likelihood that HGSOCs originate both in fimbriae and in OSE should be considered in clinical decisions involving choices between prophylactic salpingo-oophorectomies and salpingectomies.
    Full-text · Article · Apr 2013 · Gynecologic Oncology
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    • "Ovarian carcinomas are often characterised by karyotypes with severe aneuploidy due to chromosomal instability (CIN) and triploidization [13]. It has been proposed that aneuploidy is a feature of early aberrations in EOC [14]. Aneuploid tumours respond less favourably to treatment than diploid tumours, leading to lower survival rates [15]. "
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    ABSTRACT: Highly aneuploid tumours are common in epithelial ovarian cancers (EOC). We investigated whether NuMA expression was associated with this phenomenon. NuMA protein levels in normal and tumour tissues, ovarian cell lines and primary cultures of malignant cells derived from ovarian ascitic fluids were analysed by Affymetrix microarray analysis, immunoblotting, immunohistochemistry (IHC) and immunofluorescence (IF), with results correlated to associated clinical data. Aneuploidy status in primary cultures was determined by FACS analysis. Affymetrix microarray data indicated that NuMA was overexpressed in tumour tissue, primary cultures and cell lines compared to normal ovarian tissue. IHC revealed low to weak NuMA expression in normal tissues. Expression was upregulated in tumours, with a significant association with disease stage in mucinous EOC subtypes (p = 0.009), lymph node involvement (p = 0.03) and patient age (p = 0.04). Additional discontinuous data analysis revealed that high NuMA levels in tumours decreased with grade (p = 0.02) but increased with disease stage (p = 0.04) in serous EOC. NuMA expression decreased in late disease stage 4 endometrioid EOCs. High NuMA levels decreased with increased tumour invasion in all subtypes (p = 0.03). IF of primary cultures revealed that high NuMA levels at mitotic spindle poles were significantly associated with a decreased proportion of cells in cytokinesis (p = 0.05), increased binucleation (p = 0.021) and multinucleation (p = 0.007), and aneuploidy (p = 0.008). NuMA is highly expressed in EOC tumours and high NuMA levels correlate with increases in mitotic defects and aneuploidy in primary cultures.
    Full-text · Article · Jun 2012 · PLoS ONE
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