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Whole-exome sequencing of ovarian clear cell carcinoma in clinical outliers

ABSTRACT: Whole-exome sequencing dataset for the Australian Ovarian Cancer Study (AOCS) and The Jikei University School of Medicine (JIKEI) ovarian clear cell carcinoma (OCCC) clinical outliers project, representing 10 donors. Although OCCC are commonly resistant to platinum based chemotherapy, good clinical outcomes are observed in a subset of patients. Exome sequencing was performed in 10 patients who had either unusually long survival (N=5) or had a very short time to progression (N=5).

PROVIDER: EGAS00001004248 | EGA |

REPOSITORIES: EGA

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Survival Following Chemotherapy in Ovarian Clear Cell Carcinoma Is Not Associated with Pathological Misclassification of Tumor Histotype.

Takenaka Masataka M Köbel Martin M Garsed Dale W DW Fereday Sian S Pandey Ahwan A Etemadmoghadam Dariush D Hendley Joy J Kawabata Ayako A Noguchi Daito D Yanaihara Nozomu N Takahashi Hiroyuki H Kiyokawa Takako T Ikegami Masahiro M Takano Hirokuni H Isonishi Seiji S Ochiai Kazuhiko K Traficante Nadia N Gadipally Sreeja S Semple Timothy T Vassiliadis Dane D Amarasinghe Kausyalya K Li Jason J Mir Arnau Gisela G Okamoto Aikou A Friedlander Michael M Bowtell David D L DDL

Clinical cancer research : an official journal of the American Association for Cancer Research 20190409 13

<h4>Purpose</h4>Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology.<h4>Experimental design</h4>To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patie ...[more]

PMID: 30967419

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c206f97a-4770-4337-a7bd-0bf63eede603 - samples

Project description:Whole-exome sequencing dataset for the Australian Ovarian Cancer Study (AOCS) and The Jikei University School of Medicine (JIKEI) ovarian clear cell carcinoma (OCCC) clinical outliers project, representing 10 donors. Consists of 20 fastq files: one normal and one tumour from each patient.

| EGAD00001006004 | EGA

DNA Methylation Profiles of Ovarian Clear Cell Carcinoma

Project description:Background. Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC. Methods. We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied non-smooth non-negative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways. Results. Two approximately equally sized clusters that associated with several clinical features were identified. Compared to Cluster 2 (N=137), Cluster 1 cases (N=134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (p-values <0.10). Subset analyses of targeted tumor sequencing and immunohistochemical data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (p-values <0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N=369 genes) were differentially expressed across cluster in transcriptomic subset analysis (p-values <10-4). Differentially expressed genes were enriched for six immune-related pathways, including interferon alpha and gamma responses (p-values < 10-6). Conclusions. DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways. Impact. This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics.

2021-12-10 | GSE185008 | GEO

Targeting meiotic recombination 11 (MRE11) nuclease for personalization of epithelial ovarian cancer therapy

Project description:Platinum resistance is a clinical challenge in ovarian cancer. Platinating agents induce DNA damage which activate Mre11 nuclease directed DNA damage signalling and response (DDR). Upregulation of DDR may promote chemotherapy resistance. Here we have comprehensively evaluated Mre11 in epithelial ovarian cancers. In clinical cohort that received platinum- based chemotherapy (n=331), Mre11 protein overexpression was associated with aggressive phenotype and poor progression free survival (PFS) (p=0.002). In the ovarian cancer genome atlas (TCGA) cohort (n=498), Mre11 gene amplification was observed in a subset of serous tumours (5%) which correlated highly with Mre11 mRNA levels (p<0.0001). Altered Mre11 levels was linked with genome wide alterations that can influence platinum sensitivity. At the transcriptomic level (n=1259), Mre11 overexpression was associated with poor PFS (p=0.003). ROC analysis showed an area under the curve (AUC) of 0.642 for response to platinum-based chemotherapy. Pre-clinically, Mre11 depletion by gene knock down or blockade by small molecule inhibitor (Mirin) reversed platinum resistance in ovarian cancer cells and in 3D spheroid models. Importantly, Mre11 inhibition was synthetically lethal in platinum sensitive XRCC1 deficient ovarian cancer cells and 3D-spheroids. Selective cytotoxicity was associated with DNA double strand break (DSB) accumulation, S-phase cell cycle arrest and increased apoptosis. We conclude that pharmaceutical development of Mre11 inhibitors is a viable clinical strategy for platinum sensitization and synthetic lethality in ovarian cancer.

2022-07-04 | GSE160540 | GEO

Targeting meiotic recombination 11 (MRE11) nuclease for personalization of epithelial ovarian cancer therapy [2]

2022-07-04 | GSE198648 | GEO

Molecular analysis of platinum-resistant and -sensitive ovarian cacner based on RNA-Seq analysis

Project description:Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies. The most difficult issue in the treatment of ovarian cancer is the eventual development of platinum resistance. Accumulating studies have shown that circRNAs are abnormally aberrantly expressed in tumors and play critical roles in tumor growth, metastasis, stemness and resistance to therapy.To identify circRNAs that play crucial roles in maintaining the platinum resistance of ovarian cacner, we performed RNA-seq analysis in platinum-resistant（n=9） and -sensitive（n=10） ovarian cacner tissues. Candidate genes were identified by bioinformatic analysis and literature review.

2024-05-30 | GSE214302 | GEO

microRNA alterations associated to early relapse in advanced stage ovarian cancer patients (validation set)

Project description:A set of 45 surgical specimens has been profiled for miRNA expression to validate miRNA alterations associated to early relapse in advanced stage ovarian cancer patients. Fresh frozen samples were collected from a series of consecutive patients with high-grade advanced stage ovarian cancer who underwent primary surgery at INT-Milan. After surgery all patients received postoperative platinum-based chemotherapy. All patients signed an Institutional Review Board approved consent for bio-banking, clinical data collection and molecular analysis. Clinical codes: Histotype: according to WHO classification guidelines Stage: according to International Federation of Gynecological and Obstetrics (FIGO) guidelines Grading: according to WHO classification guidelines Debulking: NED: not evident disease; mRD: minimal residual disease; GRD: gross residual disease Therapy code: P: Platinum without taxanes; PT: Platinum/paclitaxel

2015-04-30 | E-GEOD-67819 | biostudies-arrayexpress

Expression profiling of ovarian cancer cell lines

Project description:Paired platinum-sensitive & platinum-resistant cell lines PEO1 and PEO4 (respectively) were derived from the same patient. Cell line cultures were profiled with the HT-HGU133a GeneChip to investigate chemotherapy resistance related expression of genes marked with different histone modifications in a primary ovarian tumour (clinical data for the primary ovarian tumour is available as Series supplementary file).

2012-10-12 | GSE41499 | GEO

Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers

Project description:To identify the gene signature accounting for the distinct clinical outcomes in ovarian clear cell cancer patients Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. Arrays analyzed using BRB ArrayTools and PathwayStudio software was used to identify the signaling pathways. Gene expression profiling was completed for 10 clear cell ovarian cancer specimens and 10 normal ovarian surface epithelium using the Affymetrix human U133 Plus 2.0 Arrays

2011-05-24 | E-GEOD-29450 | biostudies-arrayexpress

Expression profiling of ovarian cancer cell lines

2012-10-12 | E-GEOD-41499 | biostudies-arrayexpress

Whole genome characterisation of chemoresistant ovarian cancer [NanoString miRNA]

Project description:Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1. Total RNA was hybridised to NanoString miRNA Human v2.1 probes, immobilized to NanoString cartridge and analysed on the NanoString Digital Analyzer. NanoString nSolver Analysis Software was utilised to check QC metrics and extract raw miRNA counts. Expression was normalised for input using the housekeeping genes. Contributor: The Australian Ovarian Cancer Study Group

2015-05-19 | E-GEOD-65819 | biostudies-arrayexpress

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