Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA172841 | ENA |
REPOSITORIES: ENA
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Project description:Serous borderline tumours (SBOT) are a challenging group of ovarian tumours positioned between benign and malignant disease. We have profiled the DNA methylomes of 12 low grade serous carcinoma (LGSC), 19 SBOT and 16 benign serous tumours (BST) across 27,578 CpG sites to further characterise the epigenomic relationship between these subtypes of ovarian tumours. Unsupervised hierarchical clustering of DNA methylation levels showed that LGSC differ distinctly from BST, however, not from SBOT. Gene ontology analysis of genes showing differential methylation at linked CpG sites between LGSC and BST revealed significant enrichment of gene groups associated with cell adhesion, cell-cell signalling and the extracellular region consistent with a more invasive phenotype of LGSC as compared to BST. Consensus clustering highlighted differences between SBOT methylomes and returned subgroups with malignant-like or benign-like methylation profiles. Furthermore, a two loci DNA methylation signature can distinguish between these SBOT subgroups with benign-like and malignant-like methylation characteristics. Our findings indicate striking similarities between SBOT and LGSC methylomes which supports a common origin and the view that LGSC may arise from SBOT. A subgroup of SBOT can be classified into tumours with a benign-like or a malignant-like methylation profile which may help in identifying tumours more likely to progress into LGSC. Array-based methylation profiling was performed using the Infinium HumanMethylation27 BeadChip in 12 low grade serous carcinoma, 19 serous borderline tumours and 16 benign serous tumours. The reproducibility of the Infinium HumanMethylation27 BeadChips was evaluated using four biological replicates of the high grade serous ovarian cancer cell line PEO1. Differential methylation cutoff was estimated from four biological replicates by bootstrap resampling and set at Δβ ≥ 0.25 corresponding to a FDR ≤ 0.09.
2012-12-31 | E-GEOD-40105 | biostudies-arrayexpress
Project description:Serous borderline tumours (SBOT) are a challenging group of ovarian tumours positioned between benign and malignant disease. We have profiled the DNA methylomes of 12 low grade serous carcinoma (LGSC), 19 SBOT and 16 benign serous tumours (BST) across 27,578 CpG sites to further characterise the epigenomic relationship between these subtypes of ovarian tumours. Unsupervised hierarchical clustering of DNA methylation levels showed that LGSC differ distinctly from BST, however, not from SBOT. Gene ontology analysis of genes showing differential methylation at linked CpG sites between LGSC and BST revealed significant enrichment of gene groups associated with cell adhesion, cell-cell signalling and the extracellular region consistent with a more invasive phenotype of LGSC as compared to BST. Consensus clustering highlighted differences between SBOT methylomes and returned subgroups with malignant-like or benign-like methylation profiles. Furthermore, a two loci DNA methylation signature can distinguish between these SBOT subgroups with benign-like and malignant-like methylation characteristics. Our findings indicate striking similarities between SBOT and LGSC methylomes which supports a common origin and the view that LGSC may arise from SBOT. A subgroup of SBOT can be classified into tumours with a benign-like or a malignant-like methylation profile which may help in identifying tumours more likely to progress into LGSC.
2012-12-31 | GSE40105 | GEO
Project description:Epithelial ovarian cancer is morphologically and clinically heterogeneous. Transcriptional profiling has revealed molecular subtypes (referred to as M-bM-^@M-^\C-signaturesM-bM-^@M-^]) that correlate to biological as well as clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and to investigate similarities to the intrinsic molecular subtypes of breast cancer. Global gene expression profiling was performed using Illumina's HT12 Bead Arrays and applied to 59 fresh-frozen ovarian tumors. SAM analysis revealed enrichment of cell cycel processes among the malignant tumors, in line with malignant tumors being highly proliferative. The borderline tumors were split between the malignant and benign tumor clusters, indicating that borderline tumors have both malignant and benign features. Furthermore, nearest centroid classification was performed applying previously published gene profiles for the ovarian cancer C-signatures and the intrinsic breast cancer subtypes, respectively, and showed significant correlations between the malignant serous tumors and the highly aggressive C1, C2 and C4 ovarian cancer signatures, and the basal-like breast cancer subtype. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer C3 signature. The borderline tumors, on the other hand, correlated significantly to the Luminal A breast cancer subtype. These findings remained when analyzed in a large, independent dataset. The data in this study link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, including an aggressive phenotype, frequent TP53 mutations and a high degree of genomic instability, and suggest that biomarkers and targeted therapies may overlap between these subsets of ovarian and breast cancers. Finally, the link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers. Total RNA obtained from serous ovarian adenocarcinomas, adenomas and borderline tumors. Gene expression profiling using Illumina's HT12 v4 bead arrays. Application of ovarian cancer molecular subtypes and intrinsic breast cancer subtypes using nearest centroid classification. KRAS and BRAF mutation analyses in the malignant and borderline tumors.
2014-08-15 | E-GEOD-57477 | biostudies-arrayexpress
Project description:Epithelial ovarian cancer is morphologically and clinically heterogeneous. Transcriptional profiling has revealed molecular subtypes (referred to as “C-signatures”) that correlate to biological as well as clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and to investigate similarities to the intrinsic molecular subtypes of breast cancer. Global gene expression profiling was performed using Illumina's HT12 Bead Arrays and applied to 59 fresh-frozen ovarian tumors. SAM analysis revealed enrichment of cell cycel processes among the malignant tumors, in line with malignant tumors being highly proliferative. The borderline tumors were split between the malignant and benign tumor clusters, indicating that borderline tumors have both malignant and benign features. Furthermore, nearest centroid classification was performed applying previously published gene profiles for the ovarian cancer C-signatures and the intrinsic breast cancer subtypes, respectively, and showed significant correlations between the malignant serous tumors and the highly aggressive C1, C2 and C4 ovarian cancer signatures, and the basal-like breast cancer subtype. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer C3 signature. The borderline tumors, on the other hand, correlated significantly to the Luminal A breast cancer subtype. These findings remained when analyzed in a large, independent dataset. The data in this study link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, including an aggressive phenotype, frequent TP53 mutations and a high degree of genomic instability, and suggest that biomarkers and targeted therapies may overlap between these subsets of ovarian and breast cancers. Finally, the link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers.
2014-08-15 | GSE57477 | GEO
Project description:The goal of the study was to identify molecular subgroups that might predict clinical outcomes in serous epithelial ovarian cancer (EOC) patients. A second objective was to identify potential therapeutic targets for serous EOC based on improved understanding of the molecular diversity of the disease. Ovarian tissues and matched peripheral blood samples were prospectively obtained from sequential patients undergoing planned gynecologic surgery at Cedars-Sinai Medical Center between 1989 and 2005. All patients underwent surgery and received adjuvant chemotherapy with a contemporaneous standard-of-care regimen. Ovarian tissue samples (n=172) were compared to a reference pool of 106 ovarian samples. Mixed reference includes normal, benign, borderline, and malignant samples.
2013-12-26 | E-GEOD-51088 | biostudies-arrayexpress
Project description:Introduction: Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histological sub-type remains undetermined. While these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors. Methods: To explore the spectrum of genomic alterations common to mucinous tumors we performed high resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n=20) and borderline tumors (n=22). Results: Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors. Conclusions: This study is the largest and highest resolution analysis of mucinous benign and borderline tumors performed to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways. Copy number data was generated for 42 mucinous ovarian tumours (20 benign, 22 borderline). Epithelial and stromal DNA from the tumours and matched-normal lymphocyte DNA were all analysed. Processed/normalized data for the germline DNA samples are not provided because they themselves are normalised to a diploid copy number, making all the probe values 2, which is not informative.
2012-08-26 | E-GEOD-39076 | biostudies-arrayexpress
Project description:Aberrant DNA methylation (DNAm) was first linked to cancer over 25 years ago. Since then, many studies have associated hypermethylation of tumour suppressor genes and hypomethylation of oncogenes to the tumourigenic process. However, most of these studies have been limited to the analysis of promoters and CpG islands (CGIs). Recently, new technologies for whole-genome DNAm (methylome) analysis have been developed, enabling unbiased analysis of cancer methylomes. Using MeDIP-seq, we report a sequencing-based comparative methylome analysis of malignant peripheral nerve sheath tumours (MPNST), benign Neurofibromas and normal Schwann cells. Analysis of these methylomes revealed a complex landscape of DNAm alterations. Contrary to the current dogma, significant global hypomethylation was not observed in the MPNST methylome. However, a highly significant (P<10-100) directional difference in DNAm was found in satellite repeats, suggesting these repeats to be the main target for hypomethylation in MPNST. Comparative analysis of the MPNST and Schwann cell methylomes identified 101,466 cancer-associated differentially methylated regions (cDMRs). Analysis showed these cDMRs to be significantly enriched for two satellite repeat types (SATR1 and ARLM-NM-1) and suggests an association between aberrant DNAm of these sequences and transition from healthy cells to malignant disease. Significant enrichment of hypermethylated cDMRs in CGI shores (P<10-60), non-CGI-associated promoters (P<10-4) and hypomethylated cDMRs in SINE repeats (P<10-100) was also identified. Integration of DNAm and gene expression data showed that the expression pattern of genes associated with CGI shore cDMRs was able to discriminate between disease phenotypes. This study establishes MeDIP-seq as an effective method to analyse cancer methylomes. Examination of methylation profiles in malignant, benign and normal tissue
2011-01-01 | E-GEOD-21714 | biostudies-arrayexpress
Project description:Low-grade serous ovarian carcinoma is believed to arise from serous borderline ovarian tumors, yet the progression from serous borderline tumors to low-grade serous ovarian carcinoma remains poorly understood. The purpose of this study was to identify differentially expressed genes between the two groups. Expression profiles were generated from 6 human ovarian surface epithelia (HOSE), 8 serous borderline ovarian tumors (SBOT), 13 low-grade serous ovarian carcinomas (LG), and 22 high-grade serous ovarian carcinomas (HG). The anterior gradient homolog 3 (AGR3) gene was found to be highly upregulated in serous borderline ovarian tumors; this finding was validated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Anti-AGR3 immunohistochemistry was performed on an additional 56 LG and 103 HG tissues and the results were correlated with clinical data. Expression profiling determined that 1254 genes were differentially expressed (P < 0.005) between SBOT, LG and HG tumors. Serous borderline ovarian tumors exhibited robust positive staining for AGR3, with a lower percentage of tumor cells stained in LG and HG. Immunofluorescence staining indicated that AGR3 expression was limited to ciliated cells. Tumor samples with a high percentage (>10%) of AGR3 positively stained tumor cells were associated with improved longer median survival in both the LG (P = 0.013) and HG (P = 0.008) serous ovarian carcinoma groups. The progression of serous borderline ovarian tumors to low-grade serous ovarian carcinoma may involve the de-differentiation of ciliated cells. AGR3 could serve as a prognostic marker for survival in patients with low-grade and high-grade serous ovarian carcinomas. Total RNA were extracted from microdissected human ovarian surface epithelia (HOSE, n=6), and microdissected serous borderline ovarian tumors (LMP, n=8), low-grade serous ovarian carcinomas (LGOSC, n=13), and 22 high-grade serous ovarian carcinomas (HGOSC, n=22). Gene Expression profiles were then generated with commercial GeneChip Human Genome U133 Plus 2.0 Array. dChip was used to identify significant differentially expressed genes between LMP/LGOSC and HGOSC
2011-03-04 | E-GEOD-27651 | biostudies-arrayexpress
Project description:Low-grade serous ovarian carcinoma is believed to arise from serous borderline ovarian tumors, yet the progression from serous borderline tumors to low-grade serous ovarian carcinoma remains poorly understood. The purpose of this study was to identify differentially expressed genes between the two groups. Expression profiles were generated from 6 human ovarian surface epithelia (HOSE), 8 serous borderline ovarian tumors (SBOT), 13 low-grade serous ovarian carcinomas (LG), and 22 high-grade serous ovarian carcinomas (HG). The anterior gradient homolog 3 (AGR3) gene was found to be highly upregulated in serous borderline ovarian tumors; this finding was validated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Anti-AGR3 immunohistochemistry was performed on an additional 56 LG and 103 HG tissues and the results were correlated with clinical data. Expression profiling determined that 1254 genes were differentially expressed (P < 0.005) between SBOT, LG and HG tumors. Serous borderline ovarian tumors exhibited robust positive staining for AGR3, with a lower percentage of tumor cells stained in LG and HG. Immunofluorescence staining indicated that AGR3 expression was limited to ciliated cells. Tumor samples with a high percentage (>10%) of AGR3 positively stained tumor cells were associated with improved longer median survival in both the LG (P = 0.013) and HG (P = 0.008) serous ovarian carcinoma groups. The progression of serous borderline ovarian tumors to low-grade serous ovarian carcinoma may involve the de-differentiation of ciliated cells. AGR3 could serve as a prognostic marker for survival in patients with low-grade and high-grade serous ovarian carcinomas.
2011-03-04 | GSE27651 | GEO
Project description:Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Gene expression analysis was performed on five serous borderline tumors with BRAF mutation and five serous borderline tumors without BRAF mutation randomly. RNA was extracted from microdissected tumor cells. Expression profiling was carried out with Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays
2011-03-04 | E-GEOD-27659 | biostudies-arrayexpress