Comparative proteomic analysis of low stage and high stage endometrioid ovarian adenocarcinomas

Abstract

Ovarian cancer, the second most common gynecological malignancy, accounts for 3% of all cancers among women in the United States, and has a high mortality rate, largely because existing therapies for widespread disease are rarely curative. Ovarian endometrioid adenocarcinoma (OEA) accounts for about 20% of the overall incidence of all ovarian cancer. We have used proteomics profiling to characterize low stage (FIGO stage 1 or 2) versus high stage (FIGO stage 3 or 4) human OEAs. In general, the low stage tumors lacked p53 mutations and had frequent CTNNB1 , PTEN , and/or PIK3CA mutations. The high stage tumors had mutant p53, were usually high grade, and lacked mutations predicted to deregulate Wnt/Β-catenin and PI3K/Pten/Akt signaling. We utilized 2-D liquid-based separation/mass mapping techniques to elucidate molecular weight and p I measurements of the differentially expressed intact proteins. We generated 2-D protein mass maps to facilitate the analysis of protein expression between both the low stage and high stage tumors. These mass maps (over a p I range of 5.6–4.6) revealed that the low stage OEAs demonstrated protein over-expression at the lower p I ranges (p I 4.8–4.6) in comparison to the high stage tumors, which demonstrated protein over-expression in the higher p I ranges (p I 5.4–5.2). These data suggest that both low and high stage OEAs have characteristic p I signatures of abundant protein expression probably reflecting, at least in part, the different signaling pathway defects that characterize each group. In this study, the low stage OEAs were distinguishable from high stage tumors based upon the proteomic profiles. Interestingly, when only high-grade (grade 2 or 3) OEAs were included in the analysis, the tumors still tended to cluster according to stage, suggesting that the altered protein expression was not solely dependent upon tumor cell differentiation. Further, these protein profiles clearly distinguish OEA from other types of ovarian cancer at the protein level.