Abstract
Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis.
Highlights
Epithelial ovarian carcinomas (EOC) are composed of a group of heterogeneous subtypes classified by their histology and the degree of epithelial proliferation and invasion
The biological function was quantized by converting the gene expression profiles to a gene set regularity (GSR) index computed by modifying the Differential Rank Conservation (DIRAC) algorithm [3], which measured the matching degree of gene expression rankings in a given gene set between two different phenotypes, i.e., EOC and the normal ovarian tissue control in this study
In our previous study [7], we demonstrated by the GSR indices a stepwise deterioration of cellular function regularity during serous carcinoma (SC) progression from stage I to stage IV according to International Federation of Gynecology and Obstetrics (FIGO)
Summary
Epithelial ovarian carcinomas (EOC) are composed of a group of heterogeneous subtypes classified by their histology and the degree of epithelial proliferation and invasion. The type II EOC, mainly high-grade SC, displays TP53 mutation in over 80% of the cases, exhibits impaired DNA damage repair and has a more uncontrolled cell differentiation and aggressive behavior This hypothesis was based on the studies performed in the author’s laboratory and correlated with the clinical, pathologic and molecular features of the disease. The biological function was quantized by converting the gene expression profiles to a gene set regularity (GSR) index computed by modifying the DIRAC algorithm [3], which measured the matching degree of gene expression rankings in a given gene set between two different phenotypes, i.e., EOC and the normal ovarian tissue control in this study This model utilized the gene set definitions from the GO term [4] and Reactome pathway [5] databases downloaded from the Molecular Signatures Database (MSigDB) [6]. The pathogenesis of the four EOC subtypes was investigated and compared with the GSR indices by hierarchical clustering, statistical methods and exploratory factor analysis (EFA)
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