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Project description:We conducted an epigenome-wide association study (EWAS) to evaluate global DNA methylation in EOC. In a retrospective cohort of 80 primary ovarian cancers, we observed that global DNA hypermethylation was significantly associated with high-grade tumors, platinum-resistance and poor prognosis. We determined that 8,600 differentially methylated probes (DMPs) were enriched in the intergenic regions of 4,673 genes involved in small GTPases and were significantly correlated with the PI3K-AKT, MAPK, RAS, and WNT oncogenic pathways.
2021-08-11 | GSE168926 | GEO
Project description:We conducted an epigenome-wide association study (EWAS) to evaluate global DNA methylation in EOC. In a retrospective cohort of 30 HGSOC subtype primary ovarian cancers, we observed that global DNA hypermethylation was preferentially associated with recurrent HGSOC. A total of 2,969 DMPs corresponding to 1,471 genes were involved in olfactory transduction, and calcium and cAMP signaling.
2021-08-11 | GSE168921 | GEO
Project description:BackgroundIn contrast to stable genetic events, epigenetic changes are highly plastic and play crucial roles in tumor evolution and development. Epithelial ovarian cancer (EOC) is a highly heterogeneous disease that is generally associated with poor prognosis and treatment failure. Profiling epigenome-wide DNA methylation status is therefore essential to better characterize the impact of epigenetic alterations on the heterogeneity of EOC.MethodsAn epigenome-wide association study was conducted to evaluate global DNA methylation in a retrospective cohort of 80 mixed subtypes of primary ovarian cancers and 30 patients with high-grade serous ovarian carcinoma (HGSOC). Three demethylating agents, azacytidine, decitabine, and thioguanine, were tested their anti-cancer and anti-chemoresistant effects on HGSOC cells.ResultsGlobal DNA hypermethylation was significantly associated with high-grade tumors, platinum resistance, and poor prognosis. We determined that 9313 differentially methylated probes (DMPs) were enriched in their relative gene regions of 4938 genes involved in small GTPases and were significantly correlated with the PI3K-AKT, MAPK, RAS, and WNT oncogenic pathways. On the other hand, global DNA hypermethylation was preferentially associated with recurrent HGSOC. A total of 2969 DMPs corresponding to 1471 genes were involved in olfactory transduction, and calcium and cAMP signaling. Co-treatment with demethylating agents showed significant growth retardation in ovarian cancer cells through differential inductions, such as cell apoptosis by azacytidine or G2/M cell cycle arrest by decitabine and thioguanine. Notably, azacytidine and decitabine, though not thioguanine, synergistically enhanced cisplatin-mediated cytotoxicity in HGSOC cells.ConclusionsThis study demonstrates the significant association of global hypermethylation with poor prognosis and drug resistance in high-grade EOC and highlights the potential of demethylating agents in cancer treatment.
| S-EPMC8296615 | biostudies-literature
Project description:Genome-wide DNA methylome analysis identifies putative biomarkers associated with the survival of human ovarian cancers
| PRJNA714610 | ENA
Project description:Genome-wide DNA methylome analysis identifies putative biomarkers associated with the survival of human ovarian cancers [30 cases]
| PRJNA714599 | ENA
Project description:Genome-wide DNA methylome analysis identifies putative biomarkers associated with the survival of human ovarian cancers [80 cases]
| PRJNA714617 | ENA
Project description:We hypothesized that candidate dependencies for which there are small molecules that are either approved or in advanced development for a nononcology indication may represent potential therapeutic targets. To test this hypothesis, we performed genome-scale loss-of-function screens in hundreds of cancer cell lines. We found that knockout of EGLN1, which encodes prolyl hydroxylase domain-containing protein 2 (PHD2), reduced the proliferation of a subset of clear cell ovarian cancer cell lines in vitro. EGLN1-dependent cells exhibited sensitivity to the pan-EGLN inhibitor FG-4592. The response to FG-4592 was reversed by deletion of HIF1A, demonstrating that EGLN1 dependency was related to negative regulation of HIF1A. We also found that ovarian clear cell tumors susceptible to both genetic and pharmacologic inhibition of EGLN1 required intact HIF1A. Collectively, these observations identify EGLN1 as a cancer target with therapeutic potential. SIGNIFICANCE: These findings reveal a differential dependency of clear cell ovarian cancers on EGLN1, thus identifying EGLN1 as a potential therapeutic target in clear cell ovarian cancer patients.
| S-EPMC6522283 | biostudies-literature
Project description:We used a lectin chromatography/MS-based approach to screen conditioned medium from a panel of luminal (less aggressive) and triple negative (more aggressive) breast cancer cell lines (n=5/subtype). The samples were fractionated using the lectins Aleuria aurantia (AAL) and Sambucus nigra agglutinin (SNA), which recognize fucose and sialic acid, respectively. The bound fractions were enzymatically N-deglycosylated and analyzed by LC-MS/MS. In total, we identified 533 glycoproteins, ?90% of which were components of the cell surface or extracellular matrix. We observed 1011 glycosites, 100 of which were solely detected in ?3 triple negative lines. Statistical analyses suggested that a number of these glycosites were triple negative-specific and thus potential biomarkers for this tumor subtype. An analysis of RNaseq data revealed that approximately half of the mRNAs encoding the protein scaffolds that carried potential biomarker glycosites were up-regulated in triple negative vs luminal cell lines, and that a number of genes encoding fucosyl- or sialyltransferases were differentially expressed between the two subtypes, suggesting that alterations in glycosylation may also drive candidate identification. Notably, the glycoproteins from which these putative biomarker candidates were derived are involved in cancer-related processes. Thus, they may represent novel therapeutic targets for this aggressive tumor subtype.
| S-EPMC3383053 | biostudies-literature
Project description:Purpose: Inflammatory bowel disease-associated colorectal cancers (IBD-CRC) are associated with a higher mortality than sporadic colorectal cancers. The poorly defined molecular pathogenesis of IBD-CRCs limits development of effective prevention, detection, and treatment strategies. We aimed to identify biomarkers using whole-exome sequencing of IBD-CRCs to guide individualized management.Experimental Design: Whole-exome sequencing was performed on 34 formalin-fixed paraffin-embedded primary IBD-CRCs and 31 matched normal lymph nodes. Computational methods were used to identify somatic point mutations, small insertions and deletions, mutational signatures, and somatic copy number alterations. Mismatch repair status was examined.Results: Hypermutation was observed in 27% of IBD-CRCs. All hypermutated cancers were from the proximal colon; all but one of the cancers with hypermutation had defective mismatch repair or somatic mutations in the proofreading domain of DNA POLE Hypermutated IBD-CRCs had increased numbers of predicted neo-epitopes, which could be exploited using immunotherapy. We identified six distinct mutation signatures in IBD-CRCs, three of which corresponded to known mechanisms of mutagenesis. Driver genes were also identified.Conclusions: IBD-CRCs should be evaluated for hypermutation and defective mismatch repair to identify patients with a higher neo-epitope load who may benefit from immunotherapies. Prospective trials are required to determine whether IHC to detect loss of MLH1 expression in dysplastic colonic tissue could identify patients at increased risk of developing IBD-CRC. We identified mutations in genes in IBD-CRCs with hypermutation that might be targeted therapeutically. These approaches would complement and individualize surveillance and treatment programs. Clin Cancer Res; 24(20); 5133-42. ©2018 AACR.
| S-EPMC6193541 | biostudies-literature
Project description:BackgroundThe high incidence of pre-eclampsia, which affects 2-7% of all pregnancies, remains a major health concern. Detection of pre-eclampsia before the appearance of clinical symptoms is essential to allow early intervention, and would benefit from identification of plasma/serum biomarkers to help guide diagnosis and treatment. Liquid biopsy has emerged as a promising source of protein biomarkers that circumvents some of the inherent challenges of proteome-wide analysis of plasma/serum. In this respect, purified exosomes have the added benefit of being carriers of intercellular communication both in physiological and pathological conditions.MethodsWe compared the protein complement of purified exosomes from three different collections of control and pre-eclamptic serum samples, obtained at the end of the second trimester of pregnancy and at delivery. We employed shotgun label-free proteomics to investigate differential protein expression, which was then validated by targeted proteomics.ResultsWe developed a purification method that yielded highly enriched exosome preparations. The presence of specific pregnancy protein markers suggested that a significant proportion of purified exosomes derived from tissues related to pregnancy. Quantitative proteomic analyses allowed us to identify 10, 114 and 98 differentially-regulated proteins in the three sample collections, with a high degree of concordance. Functional analysis suggested that these proteins participate in biological processes related to pre-eclampsia, including angiogenesis, inflammation and cell migration. The differential abundance of 66 proteins was validated by targeted proteomics. Finally, we studied the impact of the pre-eclampsia-associated exosomes in the proteome using an in vitro cellular model.ConclusionsWe have identified and validated differential exosomal proteins in liquid biopsy of pregnant women that open new possibilities for early detection of pre-eclampsia. Additionally, the functional impact of the proteome composition of purified pre-eclamptic exosomes in target cells provides new information to better understand changes in embryo-maternal interactions and, consequently, the pathogenesis of this disease.
| S-EPMC8903615 | biostudies-literature