Gene Set-Based Functionome Analysis of Pathogenesis in Epithelial Ovarian Serous Carcinoma and the Molecular Features in Different FIGO Stages.

Chia-Ming Chang,Chi-Mu Chuang,Mong-Lien Wang,Ming-Jie Yang,Ming-Shyen Yen,Shih-Hwa Chiou,Cheng-Chang Chang

doi:10.3390/ijms17060886

Abstract

Serous carcinoma (SC) is the most common subtype of epithelial ovarian carcinoma and is divided into four stages by the Federation of Gynecologists and Obstetrics (FIGO) staging system. Currently, the molecular functions and biological processes of SC at different FIGO stages have not been quantified. Here, we conducted a whole-genome integrative analysis to investigate the functions of SC at different stages. The function, as defined by the GO term or canonical pathway gene set, was quantified by measuring the changes in the gene expressional order between cancerous and normal control states. The quantified function, i.e., the gene set regularity (GSR) index, was utilized to investigate the pathogenesis and functional regulation of SC at different FIGO stages. We showed that the informativeness of the GSR indices was sufficient for accurate pattern recognition and classification for machine learning. The function regularity presented by the GSR indices showed stepwise deterioration during SC progression from FIGO stage I to stage IV. The pathogenesis of SC was centered on cell cycle deregulation and accompanied with multiple functional aberrations as well as their interactions.

Highlights

Epithelial ovarian cancers (EOC) are classified into several subtypes of heterogeneous diseases
A total of 1236 samples were initially collected from the Gene Expression Omnibus (GEO) database, and 1029 samples remained in this study after the datasets that did not meet the criteria were removed
By converting the gene expression levels into gene expression rankings through the gene ontology terms or canonical pathway gene set, the function defined by that gene set was quantified into a gene set regularity (GSR) index

Summary

Introduction

Epithelial ovarian cancers (EOC) are classified into several subtypes of heterogeneous diseases. Serous carcinoma (SC) is the most common subtype of EOCs, accounting for approximately 70% of them [1], and has a poor prognosis with a five-year survival rate of only 10%–20%. Based on findings through surgical staging, the Federation of Gynecologists and Obstetrics (FIGO) system [2], the most commonly utilized staging system, divides SC into four stages: stage I: tumor confined to ovaries; stage II: tumor involves one or both ovaries with pelvic extension; stage III: tumor involves one or both ovaries with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes; and stage IV: distant metastasis. FIGO staging was established based on disease progression, including the primary site, lymph nodal draining and metastatic sites. A considerable number of clinical studies have shown its applicability to evaluate disease survival or the treatment response for SC

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