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Identification of prognostic signature in cancer based on DNA methylation interaction network.

ABSTRACT: BACKGROUND:The identification of prognostic biomarkers for cancer patients is essential for cancer research. These days, DNA methylation has been proved to be associated with cancer prognosis. However, there are few methods which identify the prognostic markers based on DNA methylation data systematically, especially considering the interaction among DNA methylation sites. METHODS:In this paper, we first evaluated the stabilities of microRNA, mRNA, and DNA methylation data in prognosis of cancer. After that, a rank-based method was applied to construct a DNA methylation interaction network. In this network, nodes with the largest degrees (10% of all the nodes) were selected as hubs. Cox regression was applied to select the hubs as prognostic signature. In this prognostic signature, DNA methylation levels of each DNA methylation site are correlated with the outcomes of cancer patients. After obtaining these prognostic genes, we performed the survival analysis in the training group and the test group to verify the reliability of these genes. RESULTS:We applied our method in three cancers (ovarian cancer, breast cancer and Glioblastoma Multiforme). In all the three cancers, there are more common ones of prognostic genes selected from different samples in DNA methylation data, compared with gene expression data and miRNA expression data, which indicates the DNA methylation data may be more stable in cancer prognosis. Power-law distribution fitting suggests that the DNA methylation interaction networks are scale-free. And the hubs selected from the three networks are all enriched by cancer related pathways. The gene signatures were obtained for the three cancers respectively, and survival analysis shows they can distinguish the outcomes of tumor patients in both the training data sets and test data sets, which outperformed the control signatures. CONCLUSIONS:A computational method was proposed to construct DNA methylation interaction network and this network could be used to select prognostic signatures in cancer.

SUBMITTER: Hu WL

PROVIDER: S-EPMC5763425 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Identification of prognostic signature in cancer based on DNA methylation interaction network.

Hu Wei-Lin WL Zhou Xiong-Hui XH

BMC medical genomics 20171221 Suppl 4

<h4>Background</h4>The identification of prognostic biomarkers for cancer patients is essential for cancer research. These days, DNA methylation has been proved to be associated with cancer prognosis. However, there are few methods which identify the prognostic markers based on DNA methylation data systematically, especially considering the interaction among DNA methylation sites.<h4>Methods</h4>In this paper, we first evaluated the stabilities of microRNA, mRNA, and DNA methylation data in prog ...[more]

PMID: 29322932

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Project description:Background: DNA methylation played essential roles in regulating gene expression. The impact of DNA methylation status on the occurrence and development of cancers has been well demonstrated. However, little is known about its prognostic role in breast cancer (BC). Materials: The Illumina Human Methylation450 array (450k array) data of BC was downloaded from the UCSC xena database. Transcriptomic data of BC was downloaded from the Cancer Genome Atlas (TCGA) database. Firstly, we used univariate and multivariate Cox regression analysis to screen out independent prognostic CpGs, and then we identified methylation-associated prognosis subgroups by consensus clustering. Next, a methylation prognostic model was developed using multivariate Cox analysis and was validated with the Illumina Human Methylation27 array (27k array) dataset of BC. We then screened out differentially expressed genes (DEGs) between methylation high-risk and low-risk groups and constructed a methylation-based gene prognostic signature. Further, we validated the gene signature with three subgroups of the TCGA-BRCA dataset and an external dataset GSE146558 from the Gene Expression Omnibus (GEO) database. Results: We established a methylation prognostic signature and a methylation-based gene prognostic signature, and there was a close positive correlation between them. The gene prognostic signature involved six genes: IRF2, KCNJ11, ZDHHC9, LRP11, PCMT1, and TMEM70. We verified their expression in mRNA and protein levels in BC. Both methylation and methylation-based gene prognostic signatures showed good prognostic stratification ability. The AUC values of 3-years, 5-years overall survival (OS) were 0.737, 0.744 in the methylation signature and 0.725, 0.715 in the gene signature, respectively. In the validation groups, high-risk patients were confirmed to have poorer OS. The AUC values of 3 years were 0.757, 0.735, 0.733 in the three subgroups of TCGA dataset and 0.635 in GSE146558 dataset. Conclusion: This study revealed the DNA methylation landscape and established promising methylation and methylation-based gene prognostic signatures that could serve as potential prognostic biomarkers and therapeutic targets.

Project description:Background: DNA methylation is an important epigenetic modification, which plays an important role in regulating gene expression at the transcriptional level. In tumor research, it has been found that the change of DNA methylation leads to the abnormality of gene structure and function, which can provide early warning for tumorigenesis. Our study aims to explore the relationship between the occurrence and development of tumor and the level of DNA methylation. Moreover, this study will provide a set of prognostic biomarkers, which can more accurately predict the survival and health of patients after treatment. Methods: Datasets of bladder cancer patients and control samples were collected from TCGA database, differential analysis was employed to obtain genes with differential DNA methylation levels between tumor samples and normal samples. Then the protein-protein interaction network was constructed, and the potential tumor markers were further obtained by extracting Hub genes from subnet. Cox proportional hazard regression model and survival analysis were used to construct the prognostic model and screen out the prognostic markers of bladder cancer, so as to provide reference for tumor prognosis monitoring and improvement of treatment plan. Results: In this study, we found that DNA methylation was indeed related with the occurrence of bladder cancer. Genes with differential DNA methylation could serve as potential biomarkers for bladder cancer. Through univariate and multivariate Cox proportional hazard regression analysis, we concluded that FASLG and PRKCZ can be used as prognostic biomarkers for bladder cancer. Patients can be classified into high or low risk group by using this two-gene prognostic model. By detecting the methylation status of these genes, we can evaluate the survival of patients. Conclusion: The analysis in our study indicates that the methylation status of tumor-related genes can be used as prognostic biomarkers of bladder cancer.

Project description:Background: Tumor microenvironment (TME) has been reported to have a strong association with tumor progression and therapeutic outcome, and epigenetic modifications such as DNA methylation can affect TMB and play an indispensable role in tumorigenesis. However, the potential mechanisms of TME and DNA methylation remain unclear in cervical cancer (CC). Methods: The immune and stromal scores of TME were generated by the ESTIMATE algorithm for CC patients in The Cancer Genome Atlas (TCGA) database. The TME and DNA methylation-related genes were identified by the integrative analysis of DNA promoter methylation and gene expression. The least absolute shrinkage and selection operator (LASSO) Cox regression was performed 1,000 times to further identify a nine-gene TME and DNA methylation-related prognostic signature. The signature was further validated in Gene Expression Omnibus (GEO) dataset. Then, the identified signature was integrated with the Federation International of Gynecology and Obstetrics (FIGO) stage to establish a composite prognostic nomogram. Results: CC patients with high immunity levels have better survival than those with low immunity levels. Both in the training and validation datasets, the risk score of the signature was an independent prognosis factor. The composite nomogram showed higher accuracy of prognosis and greater net benefits than the FIGO stage and the signature. The high-risk group had a significantly higher fraction of genome altered than the low-risk group. Eleven genes were significantly different in mutation frequencies between the high- and low-risk groups. Interestingly, patients with mutant TTN had better overall survival (OS) than those with wild type. Patients in the low-risk group had significantly higher tumor mutational burden (TMB) than those in the high-risk group. Taken together, the results of TMB, immunophenoscore (IPS), and tumor immune dysfunction and exclusion (TIDE) score suggested that patients in the low-risk group may have greater immunotherapy benefits. Finally, four drugs (panobinostat, lenvatinib, everolimus, and temsirolimus) were found to have potential therapeutic implications for patients with a high-risk score. Conclusions: Our findings highlight that the TME and DNA methylation-related prognostic signature can accurately predict the prognosis of CC and may be important for stratified management of patients and precision targeted therapy.

Project description:BACKGROUND:Robust and precise molecular prognostic predictors for luminal breast cancer are required. This study aimed to identify key methylation sites in luminal breast cancer, as well as precise molecular tools for predicting prognosis. METHODS:We compared methylation levels of normal and luminal breast cancer samples from The Cancer Genome Atlas dataset. The relationships among differentially methylated sites, corresponding mRNA expression levels and prognosis were further analysed. Differentially expressed genes in normal and cancerous samples were analysed, followed by the identification of prognostic signature genes. Samples were divided into low- and high-risk groups based on the signature genes. Prognoses of low- and high-risk groups were compared. The Gene Expression Omnibus dataset were used to validate signature genes for prognosis prediction. Prognosis of low- and high-risk groups in Luminal A and Luminal B samples from the TCGA and the Metabric cohort dataset were analyzed. We also analysed the correlation between clinical features of low- and high- risk groups as well as their differences in gene expression. RESULTS:Fourteen methylation sites were considered to be related to luminal breast cancer prognosis because their methylation levels, mRNA expression and prognoses were closely related to each other. The methylation level of SOSTDC1 was used to divide samples into hypo- and hyper-methylation groups. We also identified an mRNA signature, comprising eight transcripts, ESCO2, PACSIN1, CDCA2, PIGR, PTN, RGMA, KLK4 and CENPA, which was used to divide samples into low- and high-risk groups. The low-risk group showed significantly better prognosis than the high-risk group. A correlation analysis revealed that the risk score was an independent prognostic factor. Low- and high- risk groups significantly correlated with the survival ratio in Luminal A samples, but not in Luminal B samples on the basis of the TCGA and the Metabric cohort dataset. Further functional annotation demonstrated that the differentially expressed genes were mainly involved in cell cycle and cancer progression. CONCLUSIONS:We identified several key methylation sites and an mRNA signature for predicting luminal breast cancer prognosis. The signature exhibited effective and precise prediction of prognosis and may serve as a prognostic and diagnostic marker for luminal breast cancer.

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Identification of prognostic signature in cancer based on DNA methylation interaction network.

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Identification of prognostic signature in cancer based on DNA methylation interaction network.

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