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Skp2 overexpression is a p27Kip1‐independent predictor of poor prognosis in patients with biliary tract cancers

To better understand the pathogenesis of biliary tract carcinoma (ETC) and to increase the accuracy of predicting outcomes for patients with this disease, we performed molecular cytogenetic analyses of BTC cell lines and tumors to identify non‐random amplification(s) and target gene(s) within the amplicons. Among several non random chromosomal aberrations detected in BTC cell lines by comparative genomic hybridization, gain/amplification of DNA at 5p was the most frequently observed alteration. We assessed the copy number and expression status of the possible target gene SKP2 for 5p amplification in cell lines and 33 primary stage II or III tumors of BTC. SKP2 was amplified, and subsequently overexpressed in both cell lines and primary tumors of BTC. However, levels of Skp2 and p27Kip1 proteins were not correlated inversely. Heightened expression of Skp2 and reduced expression of p27Kip1 were both associated with a shorter disease‐free and/or overall survival in univariate analyses. In multivariate regression analyses, Skp2 and p27Kip1 were independent predictive factors. Those results suggest that (a) overexpression of Skp2 through an amplification mechanism may contribute to the progression of BTC, (b) not only each molecule, but also the combination of Skp2 and p27Kip1, might be a useful predictor of the prognosis of BTC, and (c) molecular targets of Skp2 other than p27Kip1 may also be important factors in the pathogenesis of this disease.