Genetic analysis of the early natural history of epithelial ovarian carcinoma.
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.


RESULTS
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
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
B
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Leitao
Mario M
MM
Levine
Douglas A
DA
Viale
Agnès
A
Olshen
Adam B
AB
Arroyo
Crispinita
C
Bogomolniy
Faina
F
Olvera
Narciso
N
Lin
Oscar
O
Soslow
Robert A
RA
Robson
Mark E
ME
Offit
Kenneth
K
Barakat
Richard R
RR
Boyd
Jeff
J
D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D055088:Early Detection of Cancer; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D011230:Precancerous Conditions / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics; D008941:Spindle Apparatus / Q000235:genetics