Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
PLoS One. 2010 Apr 26;5(4):e10358. doi: 10.1371/journal.pone.0010358.
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 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.
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.
上皮性卵巢癌（EOC）的高死亡率反映了其通常在晚期被诊断出，但由于对这种恶性肿瘤的组织起源和早期自然史存在不确定性，因此早期检测的改善受到了阻碍。
方法/主要发现：在这里，我们报告了对来自 BRCA 突变携带者和普通人群的正常人类卵巢组织和早期癌症的综合分子遗传和形态学分析，表明 EOC 通常起源于上皮包涵囊肿内的发育不良前体病变。在病理上正常的卵巢中，在上皮包涵囊肿内观察到致癌应激的分子证据。为了进一步探索卵巢肿瘤发生的潜在极早期事件，对不被认为患有卵巢癌高风险的女性的卵巢组织进行了激光弹射显微切割和基因表达谱分析。这些研究显示，与表面上皮相比，良性卵巢囊性包涵上皮具有准肿瘤表达特征，特别是在影响信号转导、细胞周期控制和有丝分裂纺锤体形成的基因方面。与该基因表达谱一致，与表面上皮相比，在组织病理学上正常的卵巢囊性上皮中观察到明显更高的细胞增殖指数（增加的细胞增殖和减少的细胞凋亡）。此外，常在上皮性包涵上皮中发现非整倍体，但不在表面上皮中发现。
结论/意义：总之，这些数据表明 EOC 通常在上皮性包涵囊肿中发生，存在可识别的发育不良前体病变，并且细胞增殖增加、细胞凋亡减少和非整倍体可能代表卵巢肿瘤发生的早期异常。
