The Potential Role of Complement System in the Progression of Ovarian Clear Cell Carcinoma Inferred from the Gene Ontology-Based Immunofunctionome Analysis.

Kuo-Min Su,Li-Chun Liu,Peng-Hui Wang,Chia-Ming Chang,Mu-Hsien Yu,Tzu-Wei Lin,Mong-Lien Wang,Ping-Hsing Tsai,Cheng-Chang Chang,Yi-Pin Yang

doi:10.3390/ijms21082824

Abstract

Ovarian clear cell carcinoma (OCCC) is the second most common epithelial ovarian carcinoma (EOC). It is refractory to chemotherapy with a worse prognosis after the preliminary optimal debulking operation, such that the treatment of OCCC remains a challenge. OCCC is believed to evolve from endometriosis, a chronic immune/inflammation-related disease, so that immunotherapy may be a potential alternative treatment. Here, gene set-based analysis was used to investigate the immunofunctionomes of OCCC in early and advanced stages. Quantified biological functions defined by 5917 Gene Ontology (GO) terms downloaded from the Gene Expression Omnibus (GEO) database were used. DNA microarray gene expression profiles were used to convert 85 OCCCs and 136 normal controls into to the functionome. Relevant offspring were as extracted and the immunofunctionomes were rebuilt at different stages by machine learning. Several dysregulated pathogenic functions were found to coexist in the immunopathogenesis of early and advanced OCCC, wherein the complement-activation-alternative-pathway may be the headmost dysfunctional immunological pathway in duality for carcinogenesis at all OCCC stages. Several immunological genes involved in the complement system had dual influences on patients’ survival, and immunohistochemistrical analysis implied the higher expression of C3a receptor (C3aR) and C5a receptor (C5aR) levels in OCCC than in controls.

Highlights

Epithelial ovarian carcinoma (EOC) is the fifth most common cause of cancer-related death in women and the most lethal gynecologic malignancy [1]
The 5917 Gene Ontology (GO) gene set definitions for annotating the functionome were downloaded from the Molecular Signatures Database (MSigDB) with the version “c5.all.v6.2.symbols.gmt”
The high frequency of ARID1A and PIK3CA mutations in Ovarian clear cell carcinoma (OCCC) theoretically results in a higher activity of the PI3K–AKT–mTOR pathway, which is believed to be a critical pathway on basis of the genomic characterization of OCCC; on the other hand, phosphoinositide 3-kinase (PI3K)-related pathways are known to be essential in the carcinogenesis of clear cell carcinoma, endometrioid carcinoma, and mucinous carcinoma [28]

Summary

Introduction

Epithelial ovarian carcinoma (EOC) is the fifth most common cause of cancer-related death in women and the most lethal gynecologic malignancy [1]. Ovarian clear cell carcinoma (OCCC) belongs to type I EOC with clinical, histopathological, and genetic features that are distinct from the other types of ovarian cancer [3]. In Asia, the incidence rate of OCCC in Japan has increased, and is over 25% overall, reaching 40% in certain populations [4]. Once OCCC progresses beyond this first stage, it is pathologically classified as high-risk (i.e., advanced stages (FIGO stage III, or even stage IV)), where adjuvant chemotherapy is recommended, even if the stage is IA. The advanced stages of OCCC are associated with persistent chemoresistance and poor prognosis compared with serous or endometrioid carcinomas, especially in the Asian population, both in terms of progression-free survival (PFS) and overall survival (OS) [8]

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