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Progression Free Survival in Ovarian Cancer is Reflected in Epigenetic DNA-Methylation Profiles

ABSTRACT: Objective: Many patients with ovarian cancer disease relapse within 6 months after adjuvant chemotherapy, with a limited prognosis. Epigenetic modifications have been shown to play an important role in tumor development and formation. Therefore, global analysis of DNA methylation patterns might reveal specific CpG sites that correlate with progression-free interval (PFI) after therapy. Methods: Twenty samples of advanced ovarian cancer with a predominantly serous papillary histological subtype were subjected to DNA methylation profiling. Illumina HumanMethylation27 BeadChip technology was used for simultaneous analysis of 27,578 CpG sites in 114,000 genes. Results: Differential DNA methylation of various cytosines correlated with PFI. However, this becomes only significant by classification according to PFI with a cutoff of 128 months. Longer survival was associated with hypomethylation at specific CpG sites (e.g. GREB1, TGIF and TOB1) and hypermethylation in other genes (e.g. TMCO5, PTPRN and GUCY2C). Gene ontology analysis revealed that differentially methylated genes were significantly overrepresented in the categories telomere organization, mesoderm development and immune regulation. Conclusion: Epigenetic modifications at specific CpG sites correlate with PFI in ovarian cancer. Therefore, such analysis might be of prognostic value.

ORGANISM(S): Homo sapiens

PROVIDER: GSE25033 | GEO | 2011/05/04

SECONDARY ACCESSION(S): PRJNA134767

REPOSITORIES: GEO

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Progression Free Survival in Ovarian Cancer is Reflected in Epigenetic DNA-Methylation Profiles

Project description:Objective: Many patients with ovarian cancer disease relapse within 6 months after adjuvant chemotherapy, with a limited prognosis. Epigenetic modifications have been shown to play an important role in tumor development and formation. Therefore, global analysis of DNA methylation patterns might reveal specific CpG sites that correlate with progression-free interval (PFI) after therapy. Methods: Twenty samples of advanced ovarian cancer with a predominantly serous papillary histological subtype were subjected to DNA methylation profiling. Illumina HumanMethylation27 BeadChip technology was used for simultaneous analysis of 27,578 CpG sites in 114,000 genes. Results: Differential DNA methylation of various cytosines correlated with PFI. However, this becomes only significant by classification according to PFI with a cutoff of 128 months. Longer survival was associated with hypomethylation at specific CpG sites (e.g. GREB1, TGIF and TOB1) and hypermethylation in other genes (e.g. TMCO5, PTPRN and GUCY2C). Gene ontology analysis revealed that differentially methylated genes were significantly overrepresented in the categories telomere organization, mesoderm development and immune regulation. Conclusion: Epigenetic modifications at specific CpG sites correlate with PFI in ovarian cancer. Therefore, such analysis might be of prognostic value. Bisulphite converted DNA from the 20 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip

2011-05-04 | E-GEOD-25033 | biostudies-arrayexpress

Epigenetic regulation of the homeobox gene MSX1 associates with platinum resistant disease in high grade serous epithelial ovarian cancer

Project description:Introduction: Although High Grade Serous Ovarian Cancer (HGSOC) is considered a chemo-responsive disease, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival of <6 months. Validated biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of resistance. Methods: Differential DNA methylation was investigated in independent tumour sets using Illumina 27K HumanMethylation arrays and validated by bisulphite pyrosequencing. Gene expression was by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction into ovarian cancer cell lines. Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in HGSOC which recur by 6 months compared to after 12 months and/or with RECIST response (p<0.05, q<0.05). A decrease in methylation at these intragenic CpG sites was significantly correlated with decreased MSX1 gene expression. Low expression of MSX1 was associated with poor progression-free survival independent of known clinical prognostic features (p=0.014). Three mutant or wild-type TP53 expressing ovarian cancer cell lines, resistant to cisplatin, have reduced MSX1 expression compared to matched parental, platinum sensitive, lines. Re-expression of MSX1 in resistant lines led to cisplatin sensitisation, increased apoptosis, increased p21 and BAX expression. However, in two TP53-null cell lines, MSX1 failed to change cisplatin sensitivity. Conclusion: Hypomethylation of MSX1 is a biomarker of resistant HGSOC disease at presentation and identifies a novel mechanism of platinum drug resistance. Bisulphite converted DNA from the 86 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2

2015-11-26 | E-GEOD-75414 | biostudies-arrayexpress

DNA methylation in mouse ovarian carcinoma ID8 cell line.

Project description:We performed DNA methylation profiling at CpG sites in ID8 mouse ovarian cancer cells.

2018-07-31 | GSE104997 | GEO

Epigenetic regulation of the homeobox gene MSX1 associates with platinum resistant disease in high grade serous epithelial ovarian cancer

2015-11-26 | GSE75414 | GEO

Correlation Between SFRP1 and Colorectal Cancer and Adenoma

Project description:In summary, our study demonstrated the methylation sites of SFRP1 gene promoter in patients with colorectal cancer and adenoma and found SFRP1_16_17_18 CpG site was good performance as a diagnostic marker of colorectal cancer.

| 2401959 | ecrin-mdr-crc

Detection of Colorectal Cancer in Peripheral Blood by Septin 9 DNA Methylation Assay

Project description:Epigenomics is developing a colon cancer screening assay based on differential methylation of specific CpG sites for the detection of early stage disease. A genome-wide methylation analysis and oligonucleotide array study using DNA from various stages of colon cancer and normal tissue have been completed to obtain candidate CpG markers. Based on results obtained in the above studies, Epigenomics has moved to the final stages of feasibility with a specific, highly sensitive real-time marker assay that is able to detect colon cancer DNA in blood plasma.

| 2056787 | ecrin-mdr-crc

Comparasion of DNA methylomes of human CD11b+ cells from healthy donors (HD) peripheral blood and CD11b+ cells isolated from ascitic fluid (a) or peripheral blood (b) from ovarian cancer patients

Project description:The methylation profiles of bisulfite-modified DNA of human CD11b+ cells from healthy donors (HD) were compared with CD11b+ cells isolated from ovarian cancer patients (blood or ascitic fluid) using the Infinium HumanMethylation850 BeadChips (Illumina, Inc., San Diego, CA,). This platform allows the interrogation of >850,000 methylation sites per sample at single-nucleotide resolution, and comprises an average of 17 CpG sites per gene in the 99% of RefSeq genes. 96% of CpG islands are covered, with additional coverage in CpG island shores and the regions flanking them. The samples were hybridized in the array following the manufacturer’s instructions.

2017-09-11 | GSE103397 | GEO

Methylomic signatures of platinum re-sensitization in ovarian cancer [Illumina HumanMethylation450 BeadChip]

Project description:Epigenetic changes, particularly DNA methylation aberrations have been implicated in acquired resistance to platinum in ovarian cancer. A multi-institutional randomized clinical trial compared a regimen of a DNA methyl transferase (DNMT) inhibitor guadecitabine and carboplatin to physician’s choice chemotherapy for patients with recurrent platinum resistant ovarian cancer. Tumor biopsies or malignant ascites were collected at day 1 of cycle 1 (pre-guadecitabine) and after two cycles of treatment (post-decitabine). The goal of the current study was to analyze guadecitabine-induced DNA methylation and gene expression changes and correlate pretreatment levels with clinical outcomes. Epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450) and RNA sequencing revealed extensive methylation and gene expression changes induced by guadecitabine in ovarian tumors. Ninety-four gene promoters were significantly hypomethylated after treatment with guadecitabine and 949 genes were differentially expressed in pre vs. post-treatment tumors. Pathways associated with immune reactivation and DNA repair were significantly altered by guadecitabine treatment. Expression levels of 1155 genes involved in 25 networks on day 1 of cycle 1 correlated with progression free survival. Increased expression of selected genes (e.g. DOK2, miR193a) silenced through promoter methylation restored platinum sensitivity in ovarian cancer cells. Together, these results support that guadecitabine altered DNA methylation and expression of genes and gene networks correlate with re-sensitization to carboplatin in ovarian cancer patients.

2018-06-05 | GSE102119 | GEO

Genomic signatures of platinum re-sensitization in ovarian cancer [RNA-Seq]

2018-06-05 | GSE102118 | GEO

Comparison of DNA methylomes of human monocyte-derived dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) generated in co-culture with ovarian carcinoma cell line (OVCAR8) during 6 days

Project description:The methylation profiles of bisulfite-modified DNA of human CD14+ monocytes-derived immature dendritic cells (GM-CSF/IL-4) were compared with myeloid-derived suppressor cells (GM-CSF/IL-4 in co-culture with ovarian carcinoma cell line (OVCAR8)) using the Infinium HumanMethylation450 BeadChips (Illumina, Inc., San Diego, CA). This platform allows the interrogation of >485,000 methylation sites per sample at single-nucleotide resolution, and comprises an average of 17 CpG sites per gene in the 99% of RefSeq genes. 96% of CpG islands are covered, with additional coverage in CpG island shores and the regions flanking them. The samples were hybridized in the array following the manufacturer’s instructions.

2017-09-11 | GSE103211 | GEO

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