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Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer.

ABSTRACT: Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Although the precise mechanism(s) underlying the development of platinum resistance in late-stage ovarian cancer patients currently remains unknown, CpG-island (CGI) methylation, a phenomenon strongly associated with aberrant gene silencing and ovarian tumorigenesis, may contribute to this devastating condition.To model the onset of drug resistance, and investigate DNA methylation and gene expression alterations associated with platinum resistance, we treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After several cycles of drug selection, the isogenic drug-sensitive and -resistant pairs were subjected to global CGI methylation and mRNA expression microarray analyses. To identify chemoresistance-associated, biological pathways likely impacted by DNA methylation, promoter CGI methylation and mRNA expression profiles were integrated and subjected to pathway enrichment analysis.Promoter CGI methylation revealed a positive association (Spearman correlation of 0.99) between the total number of hypermethylated CGIs and GI50 values (i.e., increased drug resistance) following successive cisplatin treatment cycles. In accord with that result, chemoresistance was reversible by DNA methylation inhibitors. Pathway enrichment analysis revealed hypermethylation-mediated repression of cell adhesion and tight junction pathways and hypomethylation-mediated activation of the cell growth-promoting pathways PI3K/Akt, TGF-beta, and cell cycle progression, which may contribute to the onset of chemoresistance in ovarian cancer cells.Selective epigenetic disruption of distinct biological pathways was observed during development of platinum resistance in ovarian cancer. Integrated analysis of DNA methylation and gene expression may allow for the identification of new therapeutic targets and/or biomarkers prognostic of disease response. Finally, our results suggest that epigenetic therapies may facilitate the prevention or reversal of transcriptional repression responsible for chemoresistance and the restoration of sensitivity to platinum-based chemotherapeutics.

SUBMITTER: Li M

PROVIDER: S-EPMC2712480 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer.

Li Meng M Balch Curt C Montgomery John S JS Jeong Mikyoung M Chung Jae Hoon JH Yan Pearlly P Huang Tim H M TH Kim Sun S Nephew Kenneth P KP

BMC medical genomics 20090608

<h4>Background</h4>Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Although the precise mechanism(s) underlying the development of platinum resistance in late-stage ovarian cancer patients currently remains unknown, CpG-island (CGI) methylation, a phenomenon strongly associated with abe ...[more]

PMID: 19505326

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Project description:BackgroundPapillary thyroid carcinoma (PTC) is a common endocrine neoplasm with a recent increase in incidence in many countries. Although PTC has been explored by gene expression and DNA methylation studies, the regulatory mechanisms of the methylation on the gene expression was poorly clarified. In this study, DNA methylation profile (Illumina HumanMethylation 450K) of 41 PTC paired with non-neoplastic adjacent tissues (NT) was carried out to identify and contribute to the elucidation of the role of novel genic and intergenic regions beyond those described in the promoter and CpG islands (CGI). An integrative and cross-validation analysis were performed aiming to identify molecular drivers and pathways that are PTC-related.ResultsThe comparisons between PTC and NT revealed 4995 methylated probes (88% hypomethylated in PTC) and 1446 differentially expressed transcripts cross-validated by the The Cancer Genome Atlas data. The majority of these probes was found in non-promoters regions, distant from CGI and enriched by enhancers. The integrative analysis between gene expression and DNA methylation revealed 185 and 38 genes (mainly in the promoter and body regions, respectively) with negative and positive correlation, respectively. Genes showing negative correlation underlined FGF and retinoic acid signaling as critical canonical pathways disrupted by DNA methylation in PTC. BRAF mutation was detected in 68% (28 of 41) of the tumors, which presented a higher level of demethylation (95% hypomethylated probes) compared with BRAF wild-type tumors. A similar integrative analysis uncovered 40 of 254 differentially expressed genes, which are potentially regulated by DNA methylation in BRAFV600E-positive tumors. The methylation and expression pattern of six selected genes (ERBB3, FGF1, FGFR2, GABRB2, HMGA2, and RDH5) were confirmed as altered by pyrosequencing and RT-qPCR.ConclusionsDNA methylation loss in non-promoter, poor CGI and enhancer-enriched regions was a significant event in PTC, especially in tumors harboring BRAFV600E. In addition to the promoter region, gene body and 3'UTR methylation have also the potential to influence the gene expression levels (both, repressing and inducing). The integrative analysis revealed genes potentially regulated by DNA methylation pointing out potential drivers and biomarkers related to PTC development.

Project description:BACKGROUND:Ovarian cancer is an epithelial malignancy that intrigues people for its poor outcome and lack of efficient treatment, while methylation is an important mechanism that have been recognized in many malignancies. In this study, we attempt to assess abnormally methylated gene markers and pathways in ovarian cancer by integrating three microarray datasets. METHODS:Three datasets including expression (GSE26712 and GSE66957) and methylation (GSE81224) datasets were accessed. GEO2R platform was used to detect abnormally methylated-differentially expressed genes. Protein-protein interaction (PPI) networks were built and analysed for hypermethylated and hypermethylated differentially expressed genes using Cytoscape software and Mcode app. GEPIA and cBioPortal platforms were used to validate the expression of the hub genes and the correlation between their mRNA expressions and methylation levels. Kaplan Meier-plotter platform were used to assess the prognostic significance of the hub genes. RESULTS:Six hundred eighty-one hypomethylated-upregulated genes were detected and involved in Rap1 signaling pathway, biosynthesis of amino acids, endocrine resistance, apoptosis, pathways in cancer. The hub genes were TNF, UBC, SRC, ESR1, CDK1, PECAM1, CXCR4, MUC1, IKBKG. Additionally, 337 hypermethylated-downregulated genes were detected and involved in pathways in cancer, focal adhesion, sphingolipid signaling pathway, EGFR tyrosine kinase inhibitor resistance, cellular senescence. The hub genes were BDNF, CDC42, CD44, PPP2R5C, PTEN, UBB, BMP2, FOXO1, KLHL2. TNF, ESR1, MUC1, CD44, PPP2R5C, PTEN, UBB and FOXO1 showed significant negative correlation between their mRNA expressions and methylation levels. TNF, ESR1 and FOXO1 showed prognostic significance. CONCLUSIONS:Two novel gene networks were found for ovarian cancer. TNF, ESR1, MUC1 and FOXO1 are our candidate genes that might take part in ovarian cancer progression in an epigenetic approach, TNF, ESR1 and FOXO1 may serve as potential markers for ovarian cancer prognosis evaluation.

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Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer.

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Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer.

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