Aberrant DNA methylations are markedly associated with the development of cervical cancer (CC); however, only a limited number of studies have focused on identifying the DNA methylation-driven genes in CC by integrative bioinformatics analysis to predict the prognosis of CC. In the present study, DNA methylation and transcriptome profiling data were downloaded from The Cancer Genome Atlas database. DNA methylation-driven genes were obtained using the MethylMix R package. The Database for Annotation, Visualization and Integrated Discovery and ConsensusPathDB were used to perform Gene Ontology and pathway analyses, respectively. The survival R package was used to analyze overall survival rates associated with methylation-driven genes. In total, data for 125 methylation-driven mRNAs and 38 methylation-driven long-coding RNAs (lncRNAs) were obtained. Based on the univariate and multivariate Cox regression models, it was demonstrated that FLT1 (fms-related tyrosine kinase 1) mRNA, MKI67 (marker of proliferation Ki-67), PLEKHG6 (pleckstrin homology domain containing family G with RhoGef domain member 6) and POLE2 (DNA polymerase epsilon 2) lncRNAs were predictors of the overall survival of patients with CC. According to DNA methylation and gene expression, FLT1 mRNA, and the MKI67, PLEKHG6 and POLE2 lncRNAs functioned as independent biomarkers for the prognosis of CC. DNA methylation assays revealed that the promoter methylation levels of FLT1 were significantly upregulated in CC and cervical adenocarcinoma compared with normal controls. The results of immunohistochemical analysis revealed that the expression level of FLT1 in CC tissues was higher than that in normal tissues; however, the PLEKHG6 gene was expressed at high levels in normal tissues. On the whole, the present study demonstrates that methylation-driven lncRNAs and mRNAs contribute to the survival of patients with CC, and FLT1 mRNA, and the MKI67, PLEKHG6 and POLE2 lncRNAs may be potential biomarkers for the prognosis of CC.
Cervical cancer (CC) is an extremely common malignant tumor of the female reproductive system, and the prevalence of CC is the second highest in the whole category of female malignant tumors (
The aberrant DNA hypermethylation of CpG island (CGI) promoters (promoter hypermethylation) occurs in numerous types of cancer (
Methylation-driven genes are directly responsible for carcinogenesis and are closely related to the transformation, development and invasion of cancer (
The present study identified hypomethylated and hypermethylated genes associated with specific diseases in order to obtain CC-specific long-coding RNA (lncRNA) sequences driven by methylation, and that may be used to predict the diagnosis and prognosis of patients with CC. These findings may provide new insight into the prediction of the prognosis of patients with CC, using the combination of methylation-driven lncRNAs and mRNAs.
RNA-sequencing data from 310 cases (255 cervical squamous cell carcinoma, 31 cervical adenocarcinoma, 17 cervical mucinous cystic neoplasms, 4 cervical intraepithelial neoplasia and 3 normal cervical tissues), DNA methylation data from 313 cases (257 cervical squamous, 32 cervical adenocarcinoma, 17 cervical mucinous cystic neoplasms, 4 cervical intraepithelial neoplasia and 3 normal cervical tissues) were obtained from TCGA database (
In addition to an open source platform (
Univariate Cox regression analysis was conducted to determine the association between the expression of DNA methylation-driven genes and the prognosis of patients with CC. Genes with a P-value <0.05 were regarded as prognostic methylation-driven genes and were subsequently fitted into the multivariate Cox regression analysis. A DNA methylation-driven gene-based prediction model was constructed using the linear combination of the expression levels of methylation-driven genes with coefficients (β) calculated from multivariate Cox regression as the weights. The risk score for each patient was calculated based on the following risk score formula: Risk score=expression of gene1 x β1 + expression of gene2 x β2 + …expression of genen x βn. Subsequently, patients were divided into the high- and low-risk groups by setting the median value of risk scores as the cut-off value. The overall survival (OS) of these two groups was calculated using the Kaplan-Meier method with the log-rank test. Receiver operating characteristic (ROC) curves were used to assess the predictive performance of the prognostic model and area under the curve (AUC) values were calculated. The expression patterns of DNA methylation-driven genes in this prognostic model were visualized using the ‘pheatmap’ R package (R software3.6.2, Mathsoft, Inc.).
In order to perform an in-depth assessment of methylation-driven genes associated with prognosis and survival, the clinical data of CC from TCGA were utilized to analyze the survival of the driver genes and related methylated sites. The construction of Kaplan-Meier curves was conducted to identify the association between methylation-driven genes and the survival rate of patients with CC. The prognosis of patients with CC was predicted by identifying latent methylation-driven mRNAs and methylation-driven lncRNAs.
The methylation status of the FLT1 promoter was determined using bisulfite sequencing. DNA was extracted and digested with EcoRV (Takara Bio, Inc.). The EpiTect Bisulite Kit (Qiagen, Inc.) was used to perform the bisulfite sequencing analysis with the EpiTect Bisulite kit (Qiagen, Inc.) according to the manufacturer's instructions. The transformed DNA was then PCR-amplified using the Takara Taq kit (Takara Bio, Inc.). The sequences of the primers used are presented in
A total of 25 paraffin-embedded CC tissue specimens and 15 paraffin-embedded normal cervical epithelium tissue specimens were collected from The Affiliated Hospital of Qingdao University. The present study was approved by the Institutional Review Board of the Affiliated Hospital of Qingdao University Health Science Center Ethics Committee (approval no. QYFY WZLL 25964). All patients or their patents/guardians in the present study provided written informed consent for participation in the study. The clinical parameters of the 25 patients with CC are presented in
The R statistical package (R version 3.6.2) and SPSS 23.0 software (SPSS, Inc.) were used for statistical analysis. The Student's t-test was used for comparing the methylation status of FLT1 between the groups.
DNA methylation data were extracted from 309 cervical cancer specimens, including 3 normal samples and 306 tumor samples. Using the cut-off criteria of a false discovery rate (FDR) <0.05 and logFC >1, a total of 2,916 DEGs were screened for further analysis. The gene expression data and DNA methylation data for the 2,916 DEGs were included in the MethylMix analysis with a screening criteria set as |logFC|>1, P<0.05 and Cor <-0.3. In total, 200 mRNAs and 38 lncRNAs were identified for DNA methylation in virtue of the MethylMix criteria. The methylation-driven mRNAs and lncRNAs are listed in
According to the results of the GO enrichment analysis, there were eight GO terms with statistically significant differences (P<0.05): Synaptic membrane adhesion, heterochromatin assembly, heterochromatin organization, positive regulation of cellular senescence, positive regulation of cell aging, cell-cell adhesion via plasma-membrane adhesion molecules, regulation of presynapse assembly, and the regulation of presynapse organization. ‘GO:0099560 synaptic membrane adhesion’ exhibited the highest GO biological process (
The univariate Cox regression model was conducted for identifying the prognosis in relevance to differentially methylated genes in CC and incorporated three methylation genes conspicuous relevance to the overall survival rate (P<0.05). The univariate and multivariate Cox regression model revealed that two lncRNAs were eventually related to the survival rate of patients with CC (
Based on the median risk scores, a total of 304 samples of complete survival information were classified into a high-risk group (n=152) and low-risk group (n=152). The risk score of the low-risk group was in the range of 0.5 to 1.0; 1.0 to 2.5 was the risk score attached to the high-risk group with rapid growth trends (
In accordance with the combined Kaplan-Meier curve analysis, the combined methylation and mRNA presentation of FLT1 was relevant to the OS rate of patients with CC (P=0.036;
The methylation levels of the FLT1 promoter were significantly higher in tumor tissue than in normal tissue (CC: 27.9±8.8, P=0.0008; cervical squamous carcinoma: 22.9±14.1, P=0.048; cervical adenocarcinoma: 28.6±1.9, P=0.0005) (
The results of the staining of normal cervical tissues demonstrated that FLT1 was negatively expressed in normal cervical tissues (
As precise medicine is developing rapidly, the further discovery of diagnostic and prognostic biomarkers is of utmost urgency in order to enhance the decision making for CC. Over the years, it has been found that the decreased expression of genes caused by hypomethylation plays a crucial role in the regulating and developing malignant tumors. Abnormal DNA methylation is an effective tumor marker (
DNA methylation is known as a type of covalent modification of DNA. The primary mechanism through which epigenetic modification modulates genomic function is related to the regulation of the expression of multiple differentiation-related genes in mammals (
In the present study, one mRNA and three lncRNAs were identified as independent prognostic factors for the monitoring and prognosis of CC by combining methylation, mRNA and IncRNA expression data with survival analysis. Joint survival analysis demonstrated that the low expression of FLT1 with hypermethylation was associated with a higher survival rate than the high expression of FLT1 with hypomethylation. Compared with a high expression with hypomethylation, the low expression of MKI67, PLEKH6 and POLE2 with hypermethylation was associated with a lower survival rate. As a result, lncRNA MKI67, PLEKHG6 and POLE2 may function as cancer suppressor genes under the regulation of DNA methylation, playing crucial roles in predicting the prognosis of CC.
FLT1 (VEGFR1) is a tyrosine kinase receptor with a binding affinity to VEGF-A ~10-fold higher than other kinase insert domain receptors, and it is associated with tumor growth and metastasis (
The nuclear staining of the nuclear antigen Ki-67 has the most popular application as an agent oriented with multiplication activity. Ki-67 exists within the cell nucleus all through cell-cycle stages which excluded the resting phase G0. MKI67 protein is employed as a proliferation-oriented biomarker for determining benign, malignant tumors, or the malignancy-oriented histological grade. The percentage of Ki-67-expressing cells (Ki-67 labeling index) is used for assessing the multiplication of neoplastic cells, as this increases in separating cells, culminating in cells in the M phase (
A previous study indicated that a high PLEKHG6 expression was related to a shorter survival time of patients with colorectal cancer (
Some limitations of the present study need to be acknowledged. First, the present study was based only on research data from TCGA, which may contribute to selection bias. Second, the sample size of normal controls in TCGA was relatively small, and only three non-CC patients were included for analysis from the database. Third, FLT1 protein expression was not quantified. Therefore, further studies are warranted for experimental validation.
In conclusion, based on the genomic methylation data provided by TCGA for patients with CC, 48 methylation-driven genes associated with CC were obtained through the MethylMix algorithm. Univariate and multivariate Cox regression models revealed that the prognostic survival model constructed from four aberrant methylation-driven genes, including FLT1, MKI67, PLEKHG6 and POLE2, was an independent predictor for the prognosis of patients with CC. Based on the risk model of these five methylation-driven genes, patients with CC could be divided into a high- and a low-risk group, which provides a basis for prognosis prediction and personalized treatment plans. The expression levels of the genes, FLT1, MKI67, PLEKHG6 and POLE2, may be used as independent prognostic indicators for CC. Although further experimental verification is needed, the findings presented herein provide the bioinformatic and theoretical basis for guiding the subsequent in-depth study of CC.
Not applicable.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
BL, TZ and HL wrote the manuscript. BL, YL, TZ and HL performed the experiments. BL and BH analyzed the data. FC and QL designed the experiments and revised the manuscript. BL and FC confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
The present study was approved by the Institutional Review Board of the Affiliated Hospital of Qingdao University Health Science Center Ethics Committee (approval no. QYFY WZLL 25964). All patients or their patents/guardians in the present study provided written informed consent for participation in the study.
Not applicable.
The authors declare that they have no competing interests.
MethylMix model of DNA methylation-driven genes. (A) The distribution maps illustrate the methylation states of methylated genes. The X-axis represents the degree of methylation and the Y-axis represents the number of methylated samples; the black horizontal line represents the methylation degree distribution in normal samples.
Correlation between the expression levels of selective genes and the degree of methylation. Pearson's correlation analysis revealed a negative correlation between gene expression and methylation for F11R, PTTG1, ZNF790-AS1, GYPC, THSD7A and SLIT2. The X-axis represents the methylation degree and the Y-axis represents the gene expression level. r represents the correlation coefficient of Pearson's analysis.
Heatmap of 37 methylation-driven genes in cervical cancer. (A) Expression patterns of 37 methylation-driven genes. The orange-red color represents upregulated genes and blue represents downregulated genes between tumor and normal tissues. (B) Methylation patterns of 37 methylation-driven genes. Orange red represents highly methylated genes and blue represents low methylated genes between tumor and normal tissues.
Functional enrichment analysis of methylation-driven genes in cervical cancer. (A) Gene ontology analysis of methylation-driven genes of cervical cancer. (B) Pathway analysis of methylation-driven genes of cervical cancer. The color of the inner circle represents the Z score, while the band thickness of the inner circle represents the significance of GO terms (log10-adjusted P-values). The outer circle represents the expression (log2FC) of methylation-driven mRNAs in each enriched GO term: Red dots indicate upregulated methylation-driven mRNAs, while blue dots indicate downregulated methylation-driven mRNAs. GO, Gene Ontology.
Validation of the prognostic risk signature. (A) The distributions of risk scores of patients. (B) The distributions of risk scores and overall survival status. (C) The survival analysis of the two subgroups stratified based on the median of risk scores. (D) The expression pattern of the two methylation-driven genes in low and high-risk groups. (E) ROC curve for evaluating the prediction efficiency of the prognostic signature.
Kaplan-Meier survival curves for joint survival analysis. (A) Combination of FLT1 gene methylation and expression. (B) Combination of MKI67 gene methylation and expression. (C) Combination of PLEKHG6 gene methylation and expression. (D) Combination of POLE2 gene methylation and expression. FLT1, Fms related receptor tyrosine kinase 1; MKI67, marker of proliferation Ki-67; PLEKHG6, pleckstrin homology and RhoGEF domain containing G6; POLE2, DNA polymerase epsilon 2, accessory subunit.
Methylation status of FLT1 promoter from cervical cancer clinical samples. (A) Methylation levels in normal and cervical cancer group (***P<0.01). (B) Methylation levels in normal and cervical adenocarcinoma group (*P<0.05). (C) Methylation levels in normal and cervical squamous carcinoma group (***P<0.01). (D) Volcano plot illustrating DNA methylation differences of the FLT1 promoter in adenocarcinoma tissues. (E) Volcano plot illustrating DNA methylation differences of the FLT1 promoter in squamous carcinoma tissues. (F) The methylation values of FLT1 promoter in adenocarcinoma tissues are presented as a heatmap. (G) The methylation values of the FLT1 promoter in squamous carcinoma tissues are presented as a heatmap. FLT1, Fms related receptor tyrosine kinase 1.
Validation of FLT1 and PLEKHG6 expression in human cervical cancer tissues. Compared with normal cervical tissues, the results of stains demonstrated that (A) FLT1 was highly expressed in high cervical adenocarcinoma (stage II/III/IV); (B) PLEKHG6, compared with normal tissues, the results demonstrated that no staining was detected, and the staining intensity was negative in stage II/III/IV cervical adenocarcinoma, respectively. FLT1, Fms related receptor tyrosine kinase 1; PLEKHG6, pleckstrin homology and RhoGEF domain containing G6.
Methylation-driven mRNAs.
Gene | Normal mean | Tumor mean | logFC | P-value | FDR |
---|---|---|---|---|---|
OTX1 | 0.008609738 | 2.422484869 | 8.136302547 | 0.002907656 | 0.048976629 |
HIST1H2AM | 0.01357165 | 1.050542267 | 6.274394268 | 0.002969844 | 0.048976629 |
KREMEN2 | 0.025207773 | 5.182757296 | 7.683707338 | 0.002907656 | 0.048976629 |
HIST1H2BH | 0.025716823 | 5.936443692 | 7.850742668 | 0.002907656 | 0.048976629 |
POLQ | 0.03518915 | 3.045189881 | 6.435257713 | 0.002907656 | 0.048976629 |
CLSPN | 0.03697982 | 3.388624708 | 6.517817854 | 0.002907656 | 0.048976629 |
MCM10 | 0.052274933 | 4.303523361 | 6.363255173 | 0.002907656 | 0.048976629 |
CCDC150 | 0.05328457 | 0.70413694 | 3.724066303 | 0.002969847 | 0.048976629 |
AL109811.2 | 0.058717813 | 1.204383547 | 4.358352852 | 0.002969847 | 0.048976629 |
ASPM | 0.06079877 | 5.853531897 | 6.589121431 | 0.002907656 | 0.048976629 |
CKAP2L | 0.060848407 | 4.653990218 | 6.257104882 | 0.002907656 | 0.048976629 |
E2F8 | 0.070134097 | 5.908846804 | 6.396616784 | 0.002907656 | 0.048976629 |
E2F2 | 0.07500838 | 6.683604622 | 6.477430797 | 0.002907656 | 0.048976629 |
KIF18B | 0.094850093 | 9.138667451 | 6.590190811 | 0.002907656 | 0.048976629 |
HASPIN | 0.096249443 | 2.47958553 | 4.687176983 | 0.002969847 | 0.048976629 |
HIST1H2AG | 0.115060643 | 1.913568162 | 4.055798945 | 0.002969847 | 0.048976629 |
UHRF1 | 0.124969837 | 11.78907108 | 6.559726315 | 0.002907656 | 0.048976629 |
TROAP | 0.147849247 | 11.56818612 | 6.289891966 | 0.002907656 | 0.048976629 |
DLGAP5 | 0.153893317 | 12.06073375 | 6.292243291 | 0.002907656 | 0.048976629 |
RAD54B | 0.162129053 | 1.128769995 | 2.799536996 | 0.002907656 | 0.048976629 |
NEK2 | 0.17629113 | 13.32260506 | 6.239772511 | 0.002907656 | 0.048976629 |
CENPE | 0.1779729 | 3.701522009 | 4.378389124 | 0.002969847 | 0.048976629 |
PIF1 | 0.22515228 | 3.478096936 | 3.949325149 | 0.002969847 | 0.048976629 |
KIF24 | 0.2599404 | 2.147583169 | 3.046461223 | 0.002907656 | 0.048976629 |
DDIAS | 0.284714567 | 2.745727824 | 3.269600411 | 0.002969847 | 0.048976629 |
ATAD5 | 0.291022067 | 2.476068676 | 3.088850875 | 0.002907656 | 0.048976629 |
DNA2 | 0.296769 | 3.329539141 | 3.487910197 | 0.002969847 | 0.048976629 |
ZNF296 | 0.303531533 | 4.707985191 | 3.955191474 | 0.002969847 | 0.048976629 |
FAM83D | 0.304326433 | 23.02657124 | 6.241536143 | 0.002907656 | 0.048976629 |
ECE2 | 0.383145467 | 3.429845882 | 3.16217961 | 0.002907656 | 0.048976629 |
PARPBP | 0.384524433 | 3.276042714 | 3.09080699 | 0.002907656 | 0.048976629 |
HELLS | 0.3898357 | 5.23057021 | 3.746030111 | 0.002969847 | 0.048976629 |
SGO2 | 0.412476167 | 3.403119544 | 3.044475165 | 0.002969847 | 0.048976629 |
FANCD2 | 0.435973233 | 4.350073 | 3.318728143 | 0.002907656 | 0.048976629 |
RELT | 0.442929167 | 2.479509729 | 2.48490698 | 0.002969847 | 0.048976629 |
MND1 | 0.504417033 | 6.33443716 | 3.650527537 | 0.002969847 | 0.048976629 |
BRCA1 | 0.507887067 | 4.548310873 | 3.162751223 | 0.002969847 | 0.048976629 |
C5orf34 | 0.5172911 | 2.765671281 | 2.418581417 | 0.002907656 | 0.048976629 |
CENPO | 0.5524477 | 4.275784107 | 2.952279213 | 0.002907656 | 0.048976629 |
MYBL2 | 0.552865033 | 58.36758471 | 6.72209623 | 0.002907656 | 0.048976629 |
POLE2 | 0.654987567 | 6.006028095 | 3.196871798 | 0.002907656 | 0.048976629 |
CENPL | 0.658509633 | 2.976383827 | 2.176284134 | 0.002907656 | 0.048976629 |
MARVELD2 | 0.671502467 | 5.997847346 | 3.1589802 | 0.002969847 | 0.048976629 |
CHEK1 | 0.735316333 | 5.703614173 | 2.955439456 | 0.002907656 | 0.048976629 |
OSBPL3 | 0.741138933 | 6.655781915 | 3.166792243 | 0.002907656 | 0.048976629 |
WDHD1 | 0.788465033 | 6.624031029 | 3.07059075 | 0.002969847 | 0.048976629 |
CBX8 | 0.829757267 | 3.313400315 | 1.997551252 | 0.002969847 | 0.048976629 |
TRAIP | 0.8313529 | 4.403457653 | 2.405103872 | 0.002969847 | 0.048976629 |
MYO19 | 0.956252333 | 7.737194882 | 3.016347344 | 0.002907656 | 0.048976629 |
AC145124.1 | 1.017866967 | 0.098647165 | -3.367127609 | 0.002896012 | 0.048976629 |
NUP210 | 1.106373633 | 19.89151312 | 4.168242439 | 0.002969847 | 0.048976629 |
RNU6-247P | 1.133219833 | 0.247219555 | -2.196562986 | 0.001125537 | 0.048976629 |
AC134043.2 | 1.205617333 | 0.104221029 | -3.532053754 | 0.002969788 | 0.048976629 |
MAP7 | 1.210302133 | 10.97342529 | 3.180574781 | 0.002969847 | 0.048976629 |
BRI3BP | 1.226047 | 8.72528698 | 2.831188298 | 0.002907656 | 0.048976629 |
KNSTRN | 1.267626333 | 7.984351493 | 2.655045698 | 0.002907656 | 0.048976629 |
AC009806.1 | 1.285511 | 0.145998563 | -3.138315879 | 0.002925703 | 0.048976629 |
POLE | 1.315502 | 6.201415209 | 2.236984045 | 0.002907656 | 0.048976629 |
TMEM206 | 1.379000333 | 4.893858761 | 1.82734966 | 0.002969847 | 0.048976629 |
AL133346.1 | 1.434255967 | 0.106993678 | -3.744705055 | 0.002644399 | 0.048976629 |
ESRP1 | 1.443912813 | 29.74875038 | 4.364773531 | 0.002969847 | 0.048976629 |
AC112715.1 | 1.4462248 | 0.118338606 | -3.611299114 | 0.002965719 | 0.048976629 |
CHTF18 | 1.462383 | 9.24523781 | 2.660389225 | 0.002907656 | 0.048976629 |
ECT2 | 1.4816846 | 22.15220232 | 3.90213985 | 0.002969847 | 0.048976629 |
MAPK13 | 1.501844767 | 18.86749931 | 3.651095615 | 0.002969847 | 0.048976629 |
RFTN2 | 1.595348667 | 0.31019602 | -2.362619679 | 0.002969847 | 0.048976629 |
AC109309.1 | 1.602678533 | 0.104860342 | -3.933944014 | 0.001162976 | 0.048976629 |
CHAF1B | 1.6720722 | 7.810766497 | 2.223826988 | 0.002969847 | 0.048976629 |
ZWILCH | 1.708687667 | 8.741075 | 2.354922008 | 0.002907656 | 0.048976629 |
CHEK2 | 1.774875333 | 6.630946745 | 1.901497175 | 0.002907656 | 0.048976629 |
INTS7 | 1.820999 | 9.316283118 | 2.355024353 | 0.002907656 | 0.048976629 |
SIRT7 | 1.844280333 | 6.782226856 | 1.878701077 | 0.002907656 | 0.048976629 |
AL139339.1 | 1.938017667 | 0.125707253 | -3.946441924 | 0.002879369 | 0.048976629 |
CHAF1A | 2.076047667 | 16.8995404 | 3.025072538 | 0.002907656 | 0.048976629 |
RF00265 | 2.089666333 | 0.136408423 | -3.937267965 | 0.001504763 | 0.048976629 |
NXT2 | 2.091489 | 8.301585023 | 1.988856406 | 0.002907656 | 0.048976629 |
TMEM252 | 2.106628667 | 0.19583094 | -3.42725541 | 0.002418008 | 0.048976629 |
DARS2 | 2.133191 | 11.35261951 | 2.411940173 | 0.002907656 | 0.048976629 |
BAIAP2L1 | 2.15688 | 19.55399884 | 3.180445854 | 0.002969847 | 0.048976629 |
ABCA9 | 2.19188 | 0.125320954 | -4.128469253 | 0.002907628 | 0.048976629 |
AC027682.6 | 2.313769 | 0.252232545 | -3.197418496 | 0.002969817 | 0.048976629 |
AC055874.1 | 2.3517578 | 0.117155321 | -4.327245109 | 0.000133275 | 0.048976629 |
RNU5B-4P | 2.435468 | 0.157760404 | -3.94839197 | 0.001411833 | 0.048976629 |
MIR497HG | 2.491191667 | 0.151214923 | -4.042163599 | 0.002969847 | 0.048976629 |
LINC02310 | 2.498536333 | 0.084457297 | -4.886717316 | 0.001686668 | 0.048976629 |
AJ011932.1 | 2.579065 | 0.105607893 | -4.61005856 | 0.002370969 | 0.048976629 |
RF02204 | 2.585491 | 0.113003328 | -4.516001121 | 0.00023333 | 0.048976629 |
LIG1 | 2.855578 | 17.84753708 | 2.643870302 | 0.002907656 | 0.048976629 |
DSN1 | 3.161946 | 20.01669406 | 2.662319085 | 0.002907656 | 0.048976629 |
TCF21 | 3.189872 | 0.085908038 | -5.214561602 | 0.002869776 | 0.048976629 |
MCM2 | 3.466193333 | 52.52739823 | 3.921646096 | 0.002969847 | 0.048976629 |
CACNB2 | 3.546071333 | 0.143111465 | -4.631010398 | 0.002907656 | 0.048976629 |
MAP6 | 3.770149333 | 0.232398213 | -4.019950787 | 0.002969847 | 0.048976629 |
STARD8 | 4.046868 | 0.579137356 | -2.80482833 | 0.002969847 | 0.048976629 |
DNAJC18 | 4.105557 | 0.851534115 | -2.269441731 | 0.002969847 | 0.048976629 |
ABCA8 | 4.243906 | 0.104108682 | -5.34923041 | 0.002907415 | 0.048976629 |
FEN1 | 4.245454 | 39.62434142 | 3.222396211 | 0.002907656 | 0.048976629 |
AC005180.1 | 4.319371333 | 0.10970813 | -5.299079001 | 0.002676123 | 0.048976629 |
PGM5P4 | 4.466981 | 0.061985645 | -6.171222156 | 0.001334966 | 0.048976629 |
ABCC9 | 4.678883667 | 0.183156014 | -4.675019383 | 0.002969847 | 0.048976629 |
C1QTNF7 | 4.795991667 | 0.163575051 | -4.873804526 | 0.002907556 | 0.048976629 |
CKS1B | 4.879866667 | 27.9482614 | 2.517844905 | 0.002907656 | 0.048976629 |
PLPP7 | 4.934464667 | 0.261087022 | -4.240290927 | 0.002907656 | 0.048976629 |
REEP4 | 5.081881 | 42.67654261 | 3.070008805 | 0.002907656 | 0.048976629 |
MCM5 | 5.320449333 | 29.57469622 | 2.474743353 | 0.002969847 | 0.048976629 |
CMA1 | 5.378929667 | 0.078556297 | -6.097448395 | 0.002371218 | 0.048976629 |
ZDHHC14 | 5.434402667 | 1.034312338 | -2.393449555 | 0.002969847 | 0.048976629 |
AC027449.1 | 5.444661 | 0.096116507 | -5.823914194 | 0.002281905 | 0.048976629 |
RNASEH2A | 5.474293 | 41.41412395 | 2.919378312 | 0.002907656 | 0.048976629 |
AVPR1A | 5.481554 | 0.367751649 | -3.897781233 | 0.002969847 | 0.048976629 |
KIF22 | 5.775282667 | 28.40978773 | 2.298424587 | 0.002907656 | 0.048976629 |
HSPB2 | 5.852205333 | 0.270781266 | -4.433780553 | 0.002907556 | 0.048976629 |
AC011472.4 | 5.928092667 | 0.389895757 | -3.92640764 | 0.002907599 | 0.048976629 |
JPT1 | 6.380713667 | 63.13397343 | 3.306626852 | 0.002907656 | 0.048976629 |
ALG3 | 6.436405333 | 24.27056442 | 1.914880572 | 0.002907656 | 0.048976629 |
AL049838.1 | 6.503072333 | 0.420695562 | -3.950272966 | 0.002907556 | 0.048976629 |
EBF1 | 6.611833667 | 0.442443688 | -3.901484679 | 0.002907656 | 0.048976629 |
MEF2C | 6.728852667 | 0.705862737 | -3.252900965 | 0.002969847 | 0.048976629 |
MYOCD | 6.996498667 | 0.102720679 | -6.089834575 | 0.002969601 | 0.048976629 |
ZNF25 | 7.554867 | 1.683135292 | -2.166255211 | 0.002969847 | 0.048976629 |
AL031429.2 | 7.769253533 | 0.031932759 | -7.926594995 | 0.002356484 | 0.048976629 |
VEGFD | 7.808901333 | 0.171508728 | -5.508765681 | 0.002907025 | 0.048976629 |
KIAA1522 | 7.813884333 | 51.56979363 | 2.722414467 | 0.002907656 | 0.048976629 |
RECK | 8.13414 | 0.775032279 | -3.391661519 | 0.002969847 | 0.048976629 |
CASQ2 | 8.312275667 | 0.121069969 | -6.101330542 | 0.002898258 | 0.048976629 |
LEPR | 8.325784333 | 0.674650187 | -3.625374639 | 0.002969847 | 0.048976629 |
TUBG1 | 8.337667667 | 29.424488 | 1.819301538 | 0.002969847 | 0.048976629 |
TEK | 8.535434667 | 0.677732175 | -3.654677456 | 0.002969847 | 0.048976629 |
KPNA2 | 8.540581333 | 67.03229788 | 2.972450212 | 0.002907656 | 0.048976629 |
ACTA2-AS1 | 8.612886 | 0.24691938 | -5.124384757 | 0.002969847 | 0.048976629 |
CCL14 | 8.827088333 | 0.121593624 | -6.181798153 | 0.002867082 | 0.048976629 |
AC012085.2 | 8.845370333 | 0.072649553 | -6.927824818 | 0.002798703 | 0.048976629 |
TCEAL6 | 8.920253 | 0.022519671 | -8.629755081 | 0.001402316 | 0.048976629 |
PAFAH1B3 | 8.988921333 | 49.43504549 | 2.459314251 | 0.002969847 | 0.048976629 |
AC053503.4 | 9.164009667 | 0.083320645 | -6.781161168 | 0.000164822 | 0.048976629 |
GPIHBP1 | 9.366506667 | 0.134603951 | -6.120718419 | 0.002904384 | 0.048976629 |
ATOH8 | 9.419009 | 0.448944619 | -4.390965884 | 0.002969847 | 0.048976629 |
TRPC4 | 9.738115667 | 0.145428399 | -6.065261709 | 0.002969835 | 0.048976629 |
ABCG2 | 10.176267 | 0.409445899 | -4.635391781 | 0.002907656 | 0.048976629 |
LGI4 | 10.311944 | 0.601528799 | -4.099538714 | 0.002907656 | 0.048976629 |
RANGAP1 | 10.32322533 | 44.33790046 | 2.102646666 | 0.002907656 | 0.048976629 |
AP001107.5 | 10.62646067 | 0.253305039 | -5.390641573 | 0.002901848 | 0.048976629 |
PDE2A | 10.95424967 | 0.494103392 | -4.470533898 | 0.002907656 | 0.048976629 |
GPRASP1 | 11.455003 | 0.552640084 | -4.373493819 | 0.002907656 | 0.048976629 |
MMRN1 | 12.15564167 | 0.522061313 | -4.541262989 | 0.002969847 | 0.048976629 |
MYCT1 | 12.30727667 | 0.762555452 | -4.012525498 | 0.002969847 | 0.048976629 |
TNXB | 12.857966 | 0.456718245 | -4.815214207 | 0.002907656 | 0.048976629 |
SAMD1 | 13.00907 | 41.81634958 | 1.684549296 | 0.002969847 | 0.048976629 |
SGCA | 13.19399167 | 0.197471119 | -6.062095624 | 0.002969788 | 0.048976629 |
KCNJ8 | 13.53072233 | 0.921078094 | -3.876771568 | 0.002907656 | 0.048976629 |
TIE1 | 13.80315467 | 1.427333232 | -3.273603931 | 0.002969847 | 0.048976629 |
RHOJ | 13.874021 | 1.100021946 | -3.656781762 | 0.002969847 | 0.048976629 |
HSPA12B | 14.034565 | 0.972455828 | -3.851207818 | 0.002907656 | 0.048976629 |
FGF7 | 14.537865 | 0.520324267 | -4.804260609 | 0.002969844 | 0.048976629 |
DBI | 15.14378 | 65.29300935 | 2.108203179 | 0.002907656 | 0.048976629 |
FAM110D | 16.130117 | 0.720151257 | -4.485313138 | 0.002907656 | 0.048976629 |
CNRIP1 | 16.31504667 | 0.989692338 | -4.043079194 | 0.002969847 | 0.048976629 |
FRMD6-AS2 | 16.315638 | 0.070309123 | -7.858327798 | 0.001728836 | 0.048976629 |
CXorf36 | 16.816334 | 0.861871217 | -4.286247105 | 0.002907656 | 0.048976629 |
JAM2 | 17.52046 | 0.675551827 | -4.69683039 | 0.002907656 | 0.048976629 |
CRY2 | 17.84693667 | 3.796723552 | -2.232849603 | 0.002969847 | 0.048976629 |
MITF | 18.94895667 | 1.400401072 | -3.758206439 | 0.002907656 | 0.048976629 |
ADGRL4 | 19.25257667 | 2.112064328 | -3.188325861 | 0.002969847 | 0.048976629 |
JPH2 | 19.33681 | 0.772258646 | -4.646121884 | 0.002907656 | 0.048976629 |
DACT3 | 19.65532333 | 0.624052469 | -4.977108954 | 0.002907656 | 0.048976629 |
EMCN | 19.71717233 | 0.714594377 | -4.786184296 | 0.002907656 | 0.048976629 |
MRVI1 | 20.67947667 | 1.229043436 | -4.072591867 | 0.002907656 | 0.048976629 |
TCF23 | 20.77050833 | 0.096224314 | -7.753919336 | 0.002941943 | 0.048976629 |
ADH1B | 21.589176 | 0.242721229 | -6.474864072 | 0.002935074 | 0.048976629 |
PDZRN3 | 23.89231333 | 1.010759848 | -4.563034381 | 0.002969847 | 0.048976629 |
MMRN2 | 24.07429333 | 2.602476773 | -3.209536258 | 0.002969847 | 0.048976629 |
JAM3 | 24.25990667 | 1.557027809 | -3.961707384 | 0.002907656 | 0.048976629 |
PCNA | 26.66728333 | 215.2883285 | 3.013127342 | 0.002907656 | 0.048976629 |
LDB2 | 26.84531333 | 1.120228078 | -4.582805845 | 0.002969847 | 0.048976629 |
SERTM1 | 27.00274533 | 0.295550294 | -6.513558623 | 0.002277432 | 0.048976629 |
RAB3IL1 | 28.05983667 | 2.484895139 | -3.497249734 | 0.002969847 | 0.048976629 |
ZCCHC12 | 32.23301333 | 0.38459773 | -6.389045008 | 0.002969204 | 0.048976629 |
MXRA7 | 32.36333 | 4.08448121 | -2.986135309 | 0.002969847 | 0.048976629 |
RASL12 | 35.02677333 | 1.685038159 | -4.377604925 | 0.002907656 | 0.048976629 |
PPP1R12B | 36.13469 | 2.383394038 | -3.922295126 | 0.002907656 | 0.048976629 |
PLAC9 | 36.57375667 | 1.376582116 | -4.731646243 | 0.002969847 | 0.048976629 |
RAI2 | 38.13514 | 1.739924689 | -4.454024229 | 0.002907656 | 0.048976629 |
CD34 | 38.94151 | 2.532088291 | -3.942909212 | 0.002907656 | 0.048976629 |
PODN | 39.42252 | 1.995966966 | -4.303860252 | 0.002907656 | 0.048976629 |
TBC1D1 | 39.68758333 | 6.338195114 | -2.646543739 | 0.002969847 | 0.048976629 |
RERG | 45.54668667 | 1.610461774 | -4.821799786 | 0.002907656 | 0.048976629 |
MSRB3 | 47.28062667 | 2.374195522 | -4.315738502 | 0.002907656 | 0.048976629 |
C7 | 53.39584333 | 0.747076013 | -6.159328587 | 0.00296535 | 0.048976629 |
CHRDL1 | 56.66380333 | 0.493004955 | -6.844681482 | 0.002945266 | 0.048976629 |
TNS1 | 57.79483333 | 4.231390233 | -3.771736879 | 0.002969847 | 0.048976629 |
GNG11 | 58.94997667 | 3.146258062 | -4.227782329 | 0.002907656 | 0.048976629 |
PRELP | 63.81604667 | 3.606790139 | -4.145131851 | 0.002907656 | 0.048976629 |
ITM2A | 63.81789667 | 4.108238425 | -3.957369243 | 0.002969847 | 0.048976629 |
MATN2 | 65.18636667 | 6.405312375 | -3.34722943 | 0.002969847 | 0.048976629 |
NDN | 69.41545667 | 3.558211637 | -4.286032714 | 0.002907656 | 0.048976629 |
FBLN5 | 71.73318 | 4.392540344 | -4.029513146 | 0.002907656 | 0.048976629 |
PLN | 74.64023 | 0.821842713 | -6.504947309 | 0.002907556 | 0.048976629 |
CXCL12 | 76.48481333 | 2.589450314 | -4.884455536 | 0.002907656 | 0.048976629 |
KANK2 | 91.52304 | 8.810647905 | -3.376814954 | 0.002969847 | 0.048976629 |
PGM5-AS1 | 103.9762653 | 0.153204864 | -9.406576423 | 0.001700567 | 0.048976629 |
logFC, log fold change.
Methylation-driven IncRNAs.
Gene | Normal mean | Tumor mean | logFC | P-value | Cor | Cor P-value |
---|---|---|---|---|---|---|
CTSK | 0.359953657 | 0.778931247 | 1.113684816 | 0.002907613 | -0.333186659 | 2.28E-09 |
HMGA1 | 0.336366172 | 0.114271749 | -1.557563851 | 0.002907622 | -0.346189262 | 4.83E-10 |
ZIK1 | 0.112378753 | 0.423256447 | 1.913162742 | 0.002907633 | -0.4225026 | 1.12E-14 |
PTTG1 | 0.239439619 | 0.119640652 | -1.000954214 | 0.002969791 | -0.410831811 | 6.86E-14 |
ZSCAN18 | 0.287461835 | 0.583381623 | 1.021069511 | 0.003033222 | -0.582416793 | 3.48E-29 |
CDO1 | 0.143990529 | 0.567419479 | 1.978441762 | 0.003097858 | -0.381641109 | 4.78E-12 |
F11R | 0.35962326 | 0.142571806 | -1.334797621 | 0.003097864 | -0.360185914 | 8.35E-11 |
NOVA1 | 0.070986809 | 0.549410942 | 2.952262777 | 0.003163751 | -0.359827999 | 8.74E-11 |
ZNF582 | 0.118658864 | 0.513854519 | 2.114540083 | 0.003197172 | -0.623223069 | 2.54E-34 |
DDR2 | 0.380932141 | 0.789642763 | 1.051666101 | 0.003230892 | -0.317960483 | 1.29E-08 |
CHMP4C | 0.347515219 | 0.162185406 | -1.099432153 | 0.00329935 | -0.391735829 | 1.15E-12 |
ZNF677 | 0.084379051 | 0.573297327 | 2.764326789 | 0.003299369 | -0.602084535 | 1.44E-31 |
PTPRD | 0.11697317 | 0.492863393 | 2.07501017 | 0.003440272 | -0.367446412 | 3.25E-11 |
LAMA4 | 0.26922608 | 0.581786764 | 1.111672304 | 0.003738586 | -0.343996592 | 6.31E-10 |
ZNF418 | 0.177561931 | 0.63031161 | 1.827742931 | 0.003738618 | -0.493238972 | 3.64E-20 |
CDKN2A | 0.200931093 | 0.095506903 | -1.073023924 | 0.00397755 | -0.320163484 | 1.01E-08 |
ARNTL2 | 0.366240185 | 0.155970223 | -1.231519468 | 0.00406028 | -0.321666208 | 8.53E-09 |
GYPC | 0.238177584 | 0.602450285 | 1.338804554 | 0.004060299 | -0.449701958 | 1.22E-16 |
ZNF790-AS1 | 0.039053506 | 0.358995752 | 3.200442814 | 0.004060303 | -0.579449912 | 7.72E-29 |
ZNF135 | 0.284970925 | 0.679272407 | 1.253175522 | 0.004317812 | -0.654121773 | 9.58E-39 |
AF186192.1 | 0.111066679 | 0.493975764 | 2.1530142 | 0.004497656 | -0.453585503 | 6.20E-17 |
THSD7A | 0.100507008 | 0.537490751 | 2.418943824 | 0.004684211 | -0.430102805 | 3.29E-15 |
LRFN5 | 0.08563937 | 0.514578088 | 2.587043942 | 0.00478012 | -0.356743502 | 1.30E-10 |
SPARCL1 | 0.221767893 | 0.687152496 | 1.631579789 | 0.004877773 | -0.409453404 | 8.46E-14 |
ZNF880 | 0.045439117 | 0.424736649 | 3.224561903 | 0.005286769 | -0.611950539 | 7.93E-33 |
PABPC1P4 | 0.344094877 | 0.688325541 | 1.000284629 | 0.005958452 | -0.668913704 | 4.72E-41 |
CPXM2 | 0.235657194 | 0.503267657 | 1.094636163 | 0.006575888 | -0.40452501 | 1.78E-13 |
ANGPTL1 | 0.224534915 | 0.735755194 | 1.712286021 | 0.006838515 | -0.372454964 | 1.67E-11 |
HENMT1 | 0.234654382 | 0.106237576 | -1.143243265 | 0.007536963 | -0.389308525 | 1.63E-12 |
ZNF471 | 0.069975202 | 0.453574624 | 2.696424276 | 0.00783384 | -0.690878505 | 9.82E-45 |
EMX2 | 0.098532812 | 0.321111542 | 1.704398389 | 0.007986166 | -0.338378799 | 1.24E-09 |
CTTNBP2 | 0.072730113 | 0.167092872 | 1.200025464 | 0.00845908 | -0.329763608 | 3.40E-09 |
FAXDC2 | 0.168151612 | 0.364885714 | 1.117682056 | 0.008459093 | -0.378660562 | 7.20E-12 |
CLSTN2 | 0.142064024 | 0.409902778 | 1.528740508 | 0.009128618 | -0.318465241 | 1.22E-08 |
ROR2 | 0.060251887 | 0.132899666 | 1.141259162 | 0.015707688 | -0.33512759 | 1.82E-09 |
SLIT2 | 0.156368293 | 0.407988703 | 1.383581202 | 0.020261048 | -0.42849441 | 4.27E-15 |
PREX2 | 0.08137986 | 0.399527012 | 2.295549348 | 0.020261061 | -0.364080516 | 5.05E-11 |
CTSK | 0.359953657 | 0.778931247 | 1.113684816 | 0.002907613 | -0.333186659 | 2.28E-09 |
logFC, log fold change; Cor, correlation.
Univariate Cox regression analysis of two lncRNAs associated with overall survival in patients with cervical cancer.
Genes | HR | 95% CI of HR | P-value |
---|---|---|---|
FLT1 | 0.153 | 0.0266-0.876 | 0.035 |
MKI67 | 7622606324559.52 | 3137.628-1.851E+22 | 0.007 |
HR, hazard ratio; CI, confidence interval.
Multivariate Cox regression analysis of two lncRNAs associated with the overall survival of patients with cervical cancer.
Genes | HR | 95% CI of HR | P-value |
---|---|---|---|
FLT1 | 0.158 | 0.0280-0.894 | 0.037 |
MKI67 | 9.805E+12 | 3111.326-3.09E+22 | 0.007 |
HR, hazard ratio; CI, confidence interval.