The Cancer Genome Atlas (TCGA) Network published data from the whole genome sequencing and molecular profiling using NGS and microarray in 2011. For high-grade serous ovarian cancer (HGSC), which comprises the most common histological type in epithelial ovarian cancer and usually responds well to TC chemotherapy, it was shown that HGSC does not have the definitive driver oncogene. Interestingly, however, it was also revealed that there are four subtypes in the gene expression profile, i.e., differentiated, immunoreactive, mesenchymal, and proliferative, and that patients with HGSC with the mesenchymal subtype showed the worst prognosis [18]. Such novel classification is relevant with the difference in the microenvironment of cancer cells. Recent bioinformatics and clinicopathology approaches have shown that the mesenchymal subtype accompanied by dense fibroblastic stroma is more sensitive to paclitaxel than to other drugs [19]. These findings suggest that the mesenchymal subtype may fit the weekly dose-dense TC regimen, in which a higher dose of paclitaxel than usual is given [20]. Anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, may also improve the survival of HGSC patients with the mesenchymal subtype. Thus, selection of chemotherapeutic and molecular-targeted drugs will be considered under genomic profiling analyses indicating the cancer microenvironment.

The most important factor for poor prognosis of epithelial ovarian cancer is peritoneal dissemination. Therefore, molecular and genomic analyses for the mechanisms in the special metastatic process are mandatory. Through our extensive analyses, we have demonstrated that the hypoxic microenvironment at the beginning of metastasis plays an essential role in downregulation of E-cadherin, upregulation of S100A4, followed by increased RhoA signaling, which is responsible for cancer cell metastasis, motility, and invasion [21]. RhoA inhibitors such as lovastatin have been effective in an animal model for experimental peritoneal dissemination. In addition, we also have observed the epigenetic change of the S100A4 gene in ovarian cancer cells under a hypoxic environment, which suggests “evolution” of cancer cells during progression [22]. Upregulation of VEGF is also important in the disseminated lesions for angiogenesis and immunosuppression. Therefore, each anti-cancer drug will be directed to each microenvironment and signaling of cancer cells, which continuously evolve via changes in genomics and epigenomics and gene expressions. Accordingly, we must consider now the two-dimensional map model of the cancer genome, which shows both the diversity in carcinogenesis (X-axis) and the diversity of evolution in progression (Y-axis) (Fig. 1.2). The place of each patient will be identified on the map via genomic analyses, and the right treatment will be given at the right time in the near future.