Abstract
Clear cell adenocarcinoma of the ovary (OCC) is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH) analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR; 37.0% demonstrated Met gene amplification (>4 copies), and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p<0.05). Met knockdown by shRNA resulted in reduced viability of OCC cells with Met amplification due to increased apoptosis and cellular senescence, suggesting that the Met signaling pathway plays an important role in OCC carcinogenesis. Thus, we believe that targeted inhibition of the Met pathway may be a promising treatment for OCC.
Highlights
Clear cell adenocarcinoma of the ovary (OCC) is frequently associated with endometriosis [1], and the existence of abundant free iron in endometriotic cysts due to hemorrhage is proposed as a cause of persistent oxidative stress and subsequent carcinogenesis [2]
Of the 73 OCC cases, DNA extracted from 13 tumors and 3 endometrioid adenocarcinoma samples was subjected to arraybased comparative genomic hybridization (CGH) analysis
Yamamoto et al reported Met amplification in 28% of Japanese OCC cases [13], and Rhaman et al demonstrated that ZNF217 at chromosome 20q13.2 was amplified in 20% of their OCC patients [14]
Summary
Clear cell adenocarcinoma of the ovary (OCC) is frequently associated with endometriosis [1], and the existence of abundant free iron in endometriotic cysts due to hemorrhage is proposed as a cause of persistent oxidative stress and subsequent carcinogenesis [2]. Focusing on genomic copy number change analyses, multiple studies performed by different groups using either comparative genomic hybridization (CGH) or array-based CGH analysis in OCC cases have failed to demonstrate specific gene amplification [9,10,11]. A study from the United Kingdom reported Her amplification at chromosome 17q12 in 14% of the investigated OCC cases using array-based CGH analysis [12], emphasizing the molecular heterogeneity of the tumor. We detected amplification of the AKT2 gene, which is one of the three isoforms of AKT kinase, a downstream component of the Met/PI3K signaling pathway This is the first study to report the frequent amplification of a specific gene in OCC detected by array-based CGH analysis and the first to report AKT2 amplification in OCC. We further analyzed a larger number of OCC samples in knockdown experiments to investigate the role of the Met/PI3K/AKT pathway in OCC tumorigenesis
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