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Pothuri B , Leitao MM , Levine DA , Viale A , Olshen AB , Arroyo C , Bogomolniy F , Olvera N , Lin O , Soslow RA , Robson ME , Offit K , Barakat RR , Boyd J
Genetic Analysis of the Early Natural History of Epithelial Ovarian Carcinoma
Plos One. 2010 Apr;5(4)
PMID: ISI:000277079500022    PMCID: PMCID: PMC2859950    
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Background: 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. Methodology/Principal Findings: 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 quasineoplastic 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. Conclusions/Significance: 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.
Pothuri, Bhavana Leitao, Mario M. Levine, Douglas A. Viale, Agnes Olshen, Adam B. Arroyo, Crispinita Bogomolniy, Faina Olvera, Narciso Lin, Oscar Soslow, Robert A. Robson, Mark E. Offit, Kenneth Barakat, Richard R. Boyd, Jeff National Institutes of Health [R01 CA71840]; W.M. Keck Foundation This work was funded by a grant from the National Institutes of Health, R01 CA71840, and by a grant from the W.M. Keck Foundation, http://www.wmkeck.org. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 45 Public library science; 185 berry st, ste 1300, san francisco, ca 94107 usa 588nw