Studies On Copy Number Variations And Genes Associated With Metastasis Of Ovarian Cancer

Objective: Ovarian cancer has the worst prognosis of any gynecological malignancy,and generally presents with metastasis at advanced stages.Copy number variations(CNVs)frequently contributes to the alteration of oncogenic drivers.Affymetrix CytoScan? HD chip was used to detect copy number variants(CNVs)and loss of heterozygosity(LOH)of genomic DNA to screen the genes and participated signaling pathway in metastatic ovarian cancer tissue.Methods: Affymetrix CytoScan? HD chip was used to get all CNVs and LOH,In 6 ovarian cancer samples,common and differentiated CNVs and LOH compared with 2 normal ovarian epithelial tissue were selected out.1.The genes in candidate CNVs and LOH were analyzed by DAVID online tools for gene ontology and KEGG pathway to comprehensively understand the role of candidate genes in metastatic ovarian cancer.2.STRING database was used to analyze the network of interaction pathways for these differential genes,and survival analysis of candidate genes were performed online by Kaplan-Meier plotter.3.PASTAA was used to predict transcription factors(TFs)that regulate these target genes,then construct a gene regulatory network to identify genes that have undergone significant changes in metastatic ovarian cancer,as well as key transcription factors.Results:1.In chromosome localization analysis,six cases of metastatic ovarian cancer contained chromosomal microstructural abnormalities ranging from 400 kb to 4.9 Mb,including microdeletions,microduplications,and heterozygous deletions,the most common of which were heterozygous deletions(59.02%).These microstructural abnormalities included 352 genes.The 8 chromosome contains the most genes.2.Compared with the gene profiles of 2 normal ovarian epithelium,LOH in 1p33,1p21.1,1q31.3,2p11.2,3p11.11,7q31.31,10q25.1,20q11.21,Xp22.2,Xp21.1,Xq11.1,and Gain in 8q11.21,8q23.3,8q21.13 were screened from 6 cases of metastatic ovarian cancer tissue,which may be related to ovarian cancer metastasis and invasion.These differential candidate fragments contain a total of 192 genes.3.The function of 192 genes was determined by pathway and gene ontology analysis.The genes may play an important role in transport vesicles,transforming growth factor receptor signaling pathways,and positive regulation of apoptotic signaling pathways,and mesenchymal cell differentiation.The signaling pathway involved in metastatic ovarian cancer was analyzed and significantly enriched in carbohydrate digestion and absorption,starch and sucrose metabolism,endocytosis,chronic myeloid leukemia,pancreatic cancer and other pathways.4.There are 269 interaction pairs in 192 differential proteins,and then the relationship maps are constructed based on these relationships.Ten TFs may be closely related to the high metastatic capacity of ovarian cancer.Survival analysis showed that high expression of NOL4 L,BPIFA3,CFH,BPIFB6,SUN5,COMMD7,SH2D6,and BPIFB3 were associated with poor overall survival of ovarian cancer(P < 0.05).5.In PASTAA analysis,7 differential gene-related TFs of ovarian cancer such as OCT1,CEBPA,MEF2,STAT4,P75,HNF6,ESRA and POU2AF1 were predicted(p<0.01).CFH and COMMD7 were common target gene for 7 transcription factors.Conclusion:1.High frequency of genomic CNVs in ovarian cancer may be a relevant factor in the development of ovarian cancer.1,2,3,7,8,10,20 and X chromosomes may be characteristic fragments for metastatic ovarian cancer,especially in 8 chromosomes.2.Whole-genome CNVs chip screened multiple genes that may be involved in the metastasis of ovarian cancer.Some transcription factors(such as OCT1,CEBPA)that regulate the differentially expressed genes may play an important regulatory role in the metastasis of ovarian cancer.3.The CNVs and LOH fragments detected in this study may contain oncogenes or tumor suppressor genes,especially CFH and COMMD7,which may be characteristic biomarkers,providing new clues for future research on ovarian cancer.