CaArray_cho-00156: Gene Expression in Ovarian Cancer Reflects Both Morphology and Biological Behavior
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE68600 | GEO | 2015/05/07
SECONDARY ACCESSION(S): PRJNA283195
REPOSITORIES: GEO
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Project description:Biologically and clinically meaningful tumor classification schemes have long been sought. Some malignant epithelial neoplasms, such as those in the thyroid and endometrium, exhibit more than one pattern of differentiation, each associated with distinctive clinical features and treatments. In other tissues, all carcinomas, regardless of morphological type, are treated as though they represent a single disease. To better understand the biological and clinical features seen in the four major histological types of ovarian carcinoma (OvCa), we analyzed gene expression in 113 ovarian epithelial tumors using oligonucleotide microarrays. Global views of the variation in gene expression were obtained using PCA. These analyses show that mucinous and clear cell OvCas can be readily distinguished from serous OvCas based on their gene expression profiles, regardless of tumor stage and grade. In contrast, endometrioid adenocarcinomas show significant overlap with other histological types. Although high-stage/grade tumors are generally separable from low-stage/grade tumors, clear cell OvCa has a molecular signature that distinguishes it from other poor-prognosis OvCas. Indeed, 73 genes, expressed 2- to 29-fold higher in clear cell OvCas compared with each of the other OvCa types, were identified. Collectively, the data indicate that gene expression patterns in ovarian adenocarcinomas reflect both morphological features and biological behavior. Moreover, these studies provide a foundation for the development of new type-specific diagnostic strategies and treatments for ovarian cancer. cho-00156 Assay Type: Gene Expression Provider: Affymetrix Array Designs: Hu6800 Organism: Homo sapiens (ncbitax) Material Types: synthetic_RNA, organism_part, whole_organism, total_RNA Disease States: Ovary cancer
2015-05-07 | E-GEOD-68600 | biostudies-arrayexpress
Project description:Identification of ovarian cancer (OvCa) patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22 % of the high grade OvCa tumors at diagnosis express CIP2A oncoprotein at low levels. Further, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient OvCa cells, we identified reactive oxygen species inducer APR-246, tested previously in OvCa clinical trials. Consistent with CIP2A-deficient OvCa subtype in humans, CIP2A is dispensable for development of MISIIR-Tag-driven mouse OvCa tumors. Nevertheless, CIP2A null OvCa tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the OvCa cells to APR-246 by inhibition of NF-kB activity. Accordingly, combination of APR-246 and NF-kB inhibitor compounds strongly synergized in killing of CIP2A positive OvCa cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient OvCa tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.
2022-02-02 | GSE195984 | GEO
Project description:Background: Ovarian carcinomas consist of at least five distinct diseases: high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous. Biomarker and molecular characterization may represent a more biologically relevant basis for grouping and treating this family of tumors, rather than site of origin. Molecular characteristics have become the new standard for clinical pathology, however development of tailored type-specific therapies is hampered by a failure of basic research to recognize that model systems used to study these diseases must also be stratified. Unrelated model systems do offer value for study of biochemical processes but specific cellular context needs to be applied to assess relevant therapeutic strategies. Methods: We have focused on the identification of clear cell carcinoma cell line models. A panel of 32 “ovarian cancer” cell lines has been classified into histological types using a combination of mutation profiles, IHC mutation-surrogates, and a validated immunohistochemical model. All cell lines were identity verified using STR analysis. Results: Many described ovarian clear cell lines have characteristic mutations (including ARID1A and PIK3CA) and an overall molecular/immuno-profile typical of primary tumors. Mutations in TP53 were present in the majority of high-grade serous cell lines. Advanced genomic analysis of bona-fide clear cell carcinoma cell lines also support copy number changes in typical biomarkers such at MET and HNF1B and a lack of any recurrent expressed re-arrangements. Conclusions: As with primary ovarian tumors, mutation status of cancer genes like ARID1A and TP53 and a general immuno-profile serve well for establishing histological type of ovarian cancer cell We describe specific biomarkers and molecular features to re-classify generic “ovarian carcinoma” cell lines into type specific categories. Our data supports the use of prototype clear cell lines, such as TOV21G and JHOC-5, and questions the use of SKOV3 and A2780 as models of high-grade serous carcinoma.
2013-08-01 | GSE48351 | GEO
Project description:To demonstrate the use of a whole-genome oligonucleotide array to perform expression profiling on a series of microdissected late-stage, high-grade papillary serous ovarian adenocarcinomas to establish a prognostic gene signature correlating with survival and to identify novel survival factors in ovarian cancer. Advanced stage papillary serous tumors of the ovary are responsible for the majority of ovarian cancer deaths, yet the molecular determinants modulating patient survival are poorly characterized. We identify and validate a prognostic gene expression signature correlating with survival in a series of microdissected serous ovarian tumors. Experiment Overall Design: We identified 53 advanced stage, high-grade primary tumor specimens and 10 normal ovarian surface epithelium (OSE) brushings.
2009-10-23 | E-GEOD-18520 | biostudies-arrayexpress
Project description:To demonstrate the use of a whole-genome oligonucleotide array to perform expression profiling on a series of microdissected late-stage, high-grade papillary serous ovarian adenocarcinomas to establish a prognostic gene signature correlating with survival and to identify novel survival factors in ovarian cancer. Advanced stage papillary serous tumors of the ovary are responsible for the majority of ovarian cancer deaths, yet the molecular determinants modulating patient survival are poorly characterized. We identify and validate a prognostic gene expression signature correlating with survival in a series of microdissected serous ovarian tumors.
2009-10-17 | GSE18520 | GEO
Project description:Background: Ovarian carcinomas consist of at least five distinct diseases: high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous. Biomarker and molecular characterization may represent a more biologically relevant basis for grouping and treating this family of tumors, rather than site of origin. Molecular characteristics have become the new standard for clinical pathology, however development of tailored type-specific therapies is hampered by a failure of basic research to recognize that model systems used to study these diseases must also be stratified. Unrelated model systems do offer value for study of biochemical processes but specific cellular context needs to be applied to assess relevant therapeutic strategies. Methods: We have focused on the identification of clear cell carcinoma cell line models. A panel of 32 M-bM-^@M-^\ovarian cancerM-bM-^@M-^] cell lines has been classified into histological types using a combination of mutation profiles, IHC mutation-surrogates, and a validated immunohistochemical model. All cell lines were identity verified using STR analysis. Results: Many described ovarian clear cell lines have characteristic mutations (including ARID1A and PIK3CA) and an overall molecular/immuno-profile typical of primary tumors. Mutations in TP53 were present in the majority of high-grade serous cell lines. Advanced genomic analysis of bona-fide clear cell carcinoma cell lines also support copy number changes in typical biomarkers such at MET and HNF1B and a lack of any recurrent expressed re-arrangements. Conclusions: As with primary ovarian tumors, mutation status of cancer genes like ARID1A and TP53 and a general immuno-profile serve well for establishing histological type of ovarian cancer cell We describe specific biomarkers and molecular features to re-classify generic M-bM-^@M-^\ovarian carcinomaM-bM-^@M-^] cell lines into type specific categories. Our data supports the use of prototype clear cell lines, such as TOV21G and JHOC-5, and questions the use of SKOV3 and A2780 as models of high-grade serous carcinoma. The DNA copy number of 10 ovarian cancer cell lines was examined and changes in copy number of genes whose expression is assumed to be critical to the phenotype of ovarian clear cell carcinoma was evaluated. Copy number data was estimated from signal intensity on Affmetrix SNP 6.0 arrays. Copy number ratio values were generated in Partek Genomics Suite (v 6.6) using a Partek corporation distributed baseline file of normal (2N) genomic DNA and default parameters. Post import values were corrected for localized GC content using the inbuilt Partek feature based on methods described in Diskin et al. (Nucleic Acids Research. 2008. 36:19). The characteristic "literature reported histotype" is the reported histological subtype for each cell line from the originating laboratory or cell bank (repository). The characteristic "Predicted histology" is based on parameters described in Anglesio et al. (PLOS ONE 2013. in press), including immunohistochemical phenotype, presence of typical mutations, consistency in growth characteristics, and DNA copy number. All cell lines were grown under recomended conditions, collected near confluence (80%) and not subjected to any experimental treatments or modifications.
2013-08-01 | E-GEOD-48351 | biostudies-arrayexpress
Project description:Epithelial ovarian cancer is a very heterogeneous disease and remains the most lethal gynaecological malignancy in the Western world. Rational therapeutic approaches need to account for interpatient and intratumoral heterogeneity in treatment design. Detailed characterization of in vitro models representing the different histological and molecular subtypes is therefore imperative. Strikingly, from ~100 available ovarian cancer cell lines the origin and which subtype they represent is largely unknown. We have extensively and uniformly characterized 39 ovarian cancer cell lines (with mRNA/microRNA expression, exon sequencing, dose response curves for clinically relevant therapeutics) and obtained all available information on the clinical features and tissue of origin of the original ovarian cancer to refine the putative histological subtypes. From 39 ovarian cell lines, 14 were assigned as high-grade serous, four serous-type, one low-grade serous and 20 non-serous type. Three morphological subtypes (21 Epithelial, 7 Round, 12 Spindle) were identified that showed distinct biological and molecular characteristics, including overexpression of cell movement and migration-associated genes for the Spindle subtype. Clinical validation showed a clear association of the spindle-like tumors with metastasis, advanced stage, suboptimal debulking and poor prognosis. In addition, the morphological subtypes associated with the molecular C1-6 subtypes identified by Tothill et al. [1], Spindle clustered with C1-stromal subtype, Round with C5-mesenchymal and Epithelial with C4 subtype. We provide a uniformly generated data resource for 39 ovarian cancer cell lines, the ovarian cancer cell line panel (OCCP). This should be the basis for selecting models to develop subtype specific treatment approaches, which is very much needed to prolong the survival of ovarian cancer patients. Gene expression was measured for 32 ovarian cancer cell lines using the GeneChip Human Exon 1.0 ST Array (Affymetrix). Morphological subtypes were assigned based on cell morphology, size, growth pattern and proliferation rate during culturing of the cell lines.
2014-09-18 | E-GEOD-53418 | biostudies-arrayexpress
Project description:BACKGROUND: Because of the distinct clinical presentation of early and advanced stage ovarian cancer, we aim to clarify whether these disease entities are solely separated by time of diagnosis or whether they arise from distinct molecular events. METHODS: Sixteen early and sixteen advanced stage ovarian carcinomas, matched for histological subtype and differentiation grade, were included. Genomic aberrations were compared for each early and advanced stage ovarian cancer by array comparative genomic hybridization. To study how the aberrations correlate to the clinical characteristics of the tumors we clustered tumors based on the genomic aberrations. RESULTS: The genomic aberration patterns in advanced stage cancer equalled those in early stage, but were more frequent in advanced stage (p?=?0.012). Unsupervised clustering based on genomic aberrations yielded two clusters that significantly discriminated early from advanced stage (p?=?0.001), and that did differ significantly in survival (p?=?0.002). These clusters however did give a more accurate prognosis than histological subtype or differentiation grade. CONCLUSION: This study indicates that advanced stage ovarian cancer either progresses from early stage or from a common precursor lesion but that they do not arise from distinct carcinogenic molecular events. Furthermore, we show that array comparative genomic hybridization has the potential to identify clinically distinct patients. Sixteen early and sixteen advanced stage ovarian carcinomas
2012-08-22 | E-GEOD-24418 | biostudies-arrayexpress
Project description:The functional status of the tumor repressor protein (TP53 or TRP53) is a defining feature of ovarian cancer. Mutant or null alleles of TP53 are expressed in greater than 90% of all high-grade serous adenocarcinomas. Wild type TP53 is elevated in low-grade serous adenocarcinomas in women and in our Pten/Kras/Amhr2-Cre mutant mouse model. Disruption of the Trp53 gene in this mouse model did not lead to high-grade ovarian cancer but did increase expression of estrogen receptor alpha (ERalpha; ESR1) and markedly enhanced the responsiveness of these cells to estrogen. Specifically, when Trp53 positive and Trp53 null mutant mice were treated with estradiol or vehicle, only the Trp53 null and Esr1 positive tumors respond vigorously to estradiol in vivo and exhibit features characteristic of high-grade type ovarian cancer: invasive growth into the ovarian stroma, rampant metastases to the peritoneal cavity and signs of genomic instability. Estrogen promoted and progesterone suppressed the growth of Trp53 null ovarian tumors and tumor cells injected intraperitoneally (IP), subcutaneously (SC) or when grown in matrigel. Exposure of the Trp53 depleted cells to estrogen also has a profound impact on the tumor microenvironment and immune-related events. These results led to the new paradigm that TRP53 status is related to the susceptibility of transformed ovarian surface epithelial (OSE) cells to estradiol-induced metastases and genomic instability. This novel finding is relevant not only for women during their reproductive years but also for women on hormone (estradiol) replacement therapies. A direct comparison of ovarian surface epithelia cells from two different genotype mice
2014-03-21 | E-GEOD-51095 | biostudies-arrayexpress
Project description:BACKGROUND: Because of the distinct clinical presentation of early and advanced stage ovarian cancer, we aim to clarify whether these disease entities are solely separated by time of diagnosis or whether they arise from distinct molecular events. METHODS: Sixteen early and sixteen advanced stage ovarian carcinomas, matched for histological subtype and differentiation grade, were included. Genomic aberrations were compared for each early and advanced stage ovarian cancer by array comparative genomic hybridization. To study how the aberrations correlate to the clinical characteristics of the tumors we clustered tumors based on the genomic aberrations. RESULTS: The genomic aberration patterns in advanced stage cancer equalled those in early stage, but were more frequent in advanced stage (p = 0.012). Unsupervised clustering based on genomic aberrations yielded two clusters that significantly discriminated early from advanced stage (p = 0.001), and that did differ significantly in survival (p = 0.002). These clusters however did give a more accurate prognosis than histological subtype or differentiation grade. CONCLUSION: This study indicates that advanced stage ovarian cancer either progresses from early stage or from a common precursor lesion but that they do not arise from distinct carcinogenic molecular events. Furthermore, we show that array comparative genomic hybridization has the potential to identify clinically distinct patients.
2012-08-22 | GSE24418 | GEO