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Bioinformatics analysis and identification of potential genes related to pathogenesis of cervical intraepithelial neoplasia.

ABSTRACT: The aim of this study was to explore and identify the key genes and signal pathways contributing to cervical intraepithelial neoplasia (CIN). The gene expression profiles of GSE63514 were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened performing with packages in software R. After Gene ontology terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyzing, and Gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA) was used to analyze these genes. Then sub-modules were subsequently analyzed base CIN grade, and protein-protein interaction (PPI) network of DEGs were constructed. 537 DEGs were screened in total, consisting 331 up-regulated genes and 206 down-regulated genes in CIN samples compared to normal samples. The most DEGs were enriched in chromosomal region in cellular component (CC), organelle fission inbiological process (BP) and ATPase activity in molecular function (MF). KEGG pathway enrichment analyzing found the DEGs were mainly concentrated in 10 pathways. The results of GSEA mainly enriched in 4 functional sets: E2F-Targets, G2M-Checkpoint, Mitotic-Spindle and Spermatogenesis. A total of 6 modules were identified by WCGNA. Subsequently, grey module was the highest correlation (Cor=0.78, P=5e-22) and 31 genes were taken as candidate hub genes for CIN high grade risk (weighted correlation coefficients >0.80). Finally, diagnostic analysis showed that in addition to CCDC7, the expression levels of the remaining 13 DEGs have a high diagnostic value (AUC>0.8 and P<0.05). These findings provided a new sight into the understanding of molecular functions for CIN.

SUBMITTER: Zhang X

PROVIDER: S-EPMC7052918 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Bioinformatics analysis and identification of potential genes related to pathogenesis of cervical intraepithelial neoplasia.

Zhang Xue X Bai Jian J Yuan Cheng C Long Long L Zheng Zhewen Z Wang Qingqing Q Chen Fengxia F Zhou Yunfeng Y

Journal of Cancer 20200203 8

The aim of this study was to explore and identify the key genes and signal pathways contributing to cervical intraepithelial neoplasia (CIN). The gene expression profiles of GSE63514 were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened performing with packages in software R. After Gene ontology terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyzing, and Gene set enrichment analysis (GSEA), weighted gene co-expressi ...[more]

PMID: 32127942

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Project description:Background DNA methylation is an essential factor in the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer. The aim was to investigate the diagnostic value provided by methylation biomarkers of six tumor suppressor genes (ASTN1, DLX1, ITGA4, RXFP3, SOX17 and ZNF671) for cervical precancerous lesions and cervical cancer. Methods The histological cervical specimens of 396 cases including 93 CIN1, 99 CIN2, 93 CIN3 and 111 cervical cancers were tested for methylation-specific PCR assay (GynTect®) of score and positive rate. Among them, 66 CIN1, 93 CIN2, 87 CIN3 and 72 cervical cancers were further used for paired analysis. A chi-square test was used to analyze the difference of methylation score and positive rate in cervical specimens. The paired t-test and paired chi-square test were for analyzing the methylation score and positive rate in paired CIN and cervical cancer cases. The specificity, sensitivity, odds ratio (OR) and 95% confidence interval (95% CI) of the GynTect® assay for CIN2 or worse (CIN2 +) and CIN3 or worse (CIN3 +) were evaluated. Results According to the chi-square test trend, hypermethylation increased with severity of the lesions as defined by histological grading (P = 0.000). The methylation score above 1.1 was more common in CIN2 + than in CIN1. The DNA methylation scores in the paired groups of CIN1, CIN3 and cervical cancer were significant differences (P = 0.033, 0.000 and 0.000, respectively), except for CIN2 (P = 0.171). While the positive rate of GynTect® in each paired group had no difference (all P > 0.05). The positive rate of every methylation marker in the GynTect® assay showed differences in four cervical lesion groups (all P < 0.05). The specificity of GynTect® assay for detection of CIN2 + /CIN3 + were higher than high-risk human papillomavirus test. With CIN1 as a reference, the positive status of GynTect®/ZNF671 were significantly higher in CIN2 + : odds ratio (OR) 5.271/OR 13.909, and in CIN3 + : OR 11.022/OR 39.150, (all P < 0.001). Conclusion The promoter methylation of six tumor suppressor genes is related to the severity of cervical lesions. The GynTect® assay based on cervical specimens provides diagnostic values for detecting CIN2 + and CIN3 + . Supplementary Information The online version contains supplementary material available at 10.1186/s12885-023-10628-5.

Project description:BACKGROUND: The development of cervical cancer and its high-grade precursor lesions (Cervical Intraepithelial Neoplasia grade 2/3 [CIN2/3]) result from a persistent infection with high-risk human papillomavirus (hrHPV) types and the accumulation of (epi)genetic host cell aberrations. Epidemiological studies have demonstrated variable CIN2/3 and cancer risks between different hrHPV types. Recent genomic profiling studies revealed substantial heterogeneity in the chromosomal aberrations detected in morphologically indistinguishable CIN2/3 suggestive of varying cancer risk. The current study aimed to investigate whether CIN2/3 with different hrHPV types vary with respect to their chromosomal profiles, both in terms of the number of aberrations and chromosomal loci affected. METHODS: Chromosomal profiles were determined of 43 p16INK4a-immunopositive CIN2/3 of women with long-term hrHPV infection (? 5 years). Sixteen lesions harboured HPV16, 3 HPV18, 14 HPV31, 1 HPV33, 4 HPV45, 1 HPV51, 2 HPV52 and 2 HPV58. RESULTS: Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two major clusters, characterised by either few or multiple chromosomal aberrations, respectively. A majority of 87.5% of lesions with HPV16 were in the cluster with relatively few aberrations, whereas no such unbalanced distribution was seen for lesions harbouring other hrHPV types. Analysis of the two most prevalent types (HPV16 and HPV31) in this data set revealed a three-fold increase in the number of losses in lesions with HPV31 compared to HPV16-positive lesions. In particular, losses at chromosomes 2q, 4p, 4q, 6p, 6q, 8q & 17p and gain at 1p & 1q were significantly more frequent in HPV31-positive lesions (FDR < 0.2). CONCLUSIONS: Chromosomal aberrations in CIN2/3 are at least in part related to the hrHPV type present. The relatively low number of chromosomal aberrations observed in HPV16-positive CIN2/3 suggests that the development of these lesions is less dependent on genetic insult than those caused by other types like HPV31.

Project description:BackgroundIntrauterine growth retardation (IUGR) affects approximately 10% to 15% of all pregnancies worldwide. IUGR is not only associated with stillbirth and newborn death, but also the delay of cognition in childhood and the promotion of metabolic and vascular disorders in adulthood. Figuring out the mechanism of IUGR is rather meaningful and valuable.MethodsDatasets related to IUGR were searched in the Gene Expression Omnibus website. Principal component analysis (PCA) was used for normalization. Differential expressed genes (DEGs) were screened out using the ggpot2 tool. DEGs were used to conduct Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses, and protein-protein interaction (PPI) analysis. IUGR related genes were searched in the OMIM website to look for the intersection with the DEGs. The DEGs were analyzed for tissue-specific expression by the online resource BioGPS. The results were displayed through volcano map, Venn map, box plot, heat map, and GSEA enrichment plots drawn by R language packages.ResultsEleven DEGs were screened out of 2 datasets. One hundred ninety-five genes related to IUGR in OMIM were retrieved. EGR2 was the only intersection gene that was found in both groups. Genes associated with placental tissue expression include COL17A1, HSD11B1, and LGALS14. Molecular functions of the DEGs are related to the oxidoreductase activity. The following 4 signaling pathways, reactome signaling by interleukins, reactome collagen degradation, Naba secreted factors, and PID NFAT tfpathway, were enriched by GSEA. Two critical modules comprising 5 up-regulated genes (LEP, PRL, TAC3, MMP14, and ADAMTS4) and 4 down-regulated genes (TIMP4, FOS, CCK, and KISS1) were identified by PPI analysis. Finally, we identified 6 genes (PRL, LGALS14, EGR2, TAC3, LEP, and KISS1) that are potentially relevant to the pathophysiology of IUGR.ConclusionThe candidate down-regulated genes LGALS14 and KISS1, as well as the up-regulated genes PRL, EGR2, TAC3, and LEP, were found to be closely related to IUGR by bioinformatics analysis. These hub genes are related to hypoxia and oxidoreductase activities in placental development. We provide useful and novel information to explore the potential mechanism of IUGR and make efforts to the prevention of IUGR.

Dataset Information

Bioinformatics analysis and identification of potential genes related to pathogenesis of cervical intraepithelial neoplasia.

Publications

Bioinformatics analysis and identification of potential genes related to pathogenesis of cervical intraepithelial neoplasia.

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