title: Gene Set-Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer.
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.
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei 112, Taiwan. cm_chang@vghtpe.gov.tw.|School of Medicine, National Yang-Ming University, Taipei 112, Taiwan. cm_chang@vghtpe.gov.tw.|Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan. cm_chang@vghtpe.gov.tw.
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Chang
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei 112, Taiwan. cmjuang@gmail.com.|Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan. cmjuang@gmail.com.|Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan. cmjuang@gmail.com.
authors.forename: Chi-Mu
authors.initials: CM
authors.lastname: Chuang
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei 112, Taiwan. monglien@gmail.com.|Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan. monglien@gmail.com.
authors.forename: Mong-Lien
authors.initials: ML
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan. molly0103@gmail.com.|Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan. molly0103@gmail.com.|Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan. molly0103@gmail.com.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Yang
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei 112, Taiwan. chuangjenhua5@gmail.com.|Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan. chuangjenhua5@gmail.com.
authors.forename: Jen-Hua
authors.initials: JH
authors.lastname: Chuang
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei 112, Taiwan. mjyang@vghtpe.gov.tw.|Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan. mjyang@vghtpe.gov.tw.
authors.forename: Ming-Jie
authors.initials: MJ
authors.lastname: Yang
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei 112, Taiwan. msyen@vghtpe.gov.tw.|Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan. msyen@vghtpe.gov.tw.
authors.forename: Ming-Shyen
authors.initials: MS
authors.lastname: Yen
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei 112, Taiwan. shchiou@vghtpe.gov.tw.|Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan. shchiou@vghtpe.gov.tw.|Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan. shchiou@vghtpe.gov.tw.|Department & Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan. shchiou@vghtpe.gov.tw.
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.affiliation: Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan. obsgynchang@gmail.com.
authors.forename: Cheng-Chang
authors.initials: CC
authors.lastname: Chang
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D030541:Databases, Genetic; D015536:Down-Regulation / Q000235:genetics; D005163:Factor Analysis, Statistical; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D052138:Genes, Neoplasm; D006801:Humans; D000069550:Machine Learning; D009375:Neoplasms, Glandular and Epithelial / Q000145:classification* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000145:classification* / Q000235:genetics*; D059467:Transcriptome; D015854:Up-Regulation / Q000235:genetics
keywords: epithelial ovarian cancer; function; gene expression microarray; gene set; integrative analysis; machine learning