The genomic landscape of early stage ovarian high grade serous carcinoma
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ABSTRACT:
PROVIDER: EGAS00001005567 | EGA |
REPOSITORIES: EGA
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Project description:Our study presents the first genetic models of de novo high-grade serous carcinomas (HGSC) that originate in fallopian tube secretory epithelial cells and recapitulate the key genetic alterations and precursor lesions characteristic of human invasive ovarian cancer. Genomic copy number analysis, using array CGH, was performed on murine tumors in order to compare the overlap of copy number alterations between HGSC models and TCGA data. Array CGH was performed on genomic DNA isolated from murine HGSC tumors. Genomic DNA from three normal mouse fallopian tubes was pooled and used as the reference.
2013-12-17 | E-GEOD-49827 | biostudies-arrayexpress
Project description:Our study presents the first genetic models of de novo high-grade serous carcinomas (HGSC) that originate in fallopian tube secretory epithelial cells and recapitulate the key genetic alterations and precursor lesions characteristic of human invasive ovarian cancer. Genomic copy number analysis, using array CGH, was performed on murine tumors in order to compare the overlap of copy number alterations between HGSC models and TCGA data.
2013-12-17 | GSE49827 | GEO
Project description:Lung cancer, of which more than 80% is non-small cell, is the leading cause of cancer-related death in the United States. Copy number alterations (CNAs) in lung cancer have been shown to be positionally clustered in certain genomic regions. However, it remains unclear whether genes with copy number changes are functionally clustered. Using a dense single nucleotide polymorphism array, we performed genome-wide copy number analyses of a large collection of non-small cell lung tumors (n = 301). We proposed a formal statistical test for CNAs between different groups (e.g., noninvolved lung vs. tumors, early vs. late stage tumors). We also customized the gene set enrichment analysis (GSEA) algorithm to investigate the overrepresentation of genes with CNAs in predefined biological pathways and gene sets (i.e., functional clustering). We found that CNAs events increase substantially from germline, early stage to late stage tumor. In addition to genomic position, CNAs tend to occur away from the gene locations, especially in germline, noninvolved tissue and early stage tumors. Such tendency decreases from germline to early stage and then to late stage tumors, suggesting a relaxation of selection during tumor progression. Furthermore, genes with CNAs in non-small cell lung tumors were enriched in certain gene sets and biological pathways that play crucial roles in oncogenesis and cancer progression, demonstrating the functional aspect of CNAs in the context of biological pathways that were overlooked previously. We conclude that CNAs increase with disease progression and CNAs are both positionally and functionally clustered. The potential functional capabilities acquired via CNAs may be sufficient for normal cells to transform into malignant cells.
2011-12-06 | GSE34140 | GEO
Project description:Integration of genomic copy number analysis (Affymetrix SNP6.0 arrays) and oncogenic RAS/RAF mutation status with clinical features and tumour progression. This study found that loss of the 9p and the CDKN2A locus with the most significantly enriched copy number aberration distinguishing serous border tumors from low grade serous carcinomas, suggesting this is a key step to tumor progression. Epithelial tissue from 57 serous borderline tumors (SBTs), 19 low grade serous carcinomas (LGSC)(data for 4 of the carcinomas have previously been submitted to GEO - Series GSE19539) and 355 high grade serous carinomas (HGSC)(TCGA, 2011; GSE19539; and 8 new) were analysed for copy number aberrations using Affymetrix SNP6.0 arrays and normalised SNP6.0 data. Stromal tissue from 38 SBT and 1 HGSC were analysed for copy number aberrations using Affymetrix SNP6.0 arrays. Matching lymphocyte DNA was availabe for 54 SBT, 3 LGSC and 1 HGSC. Sanger sequencing of KRAS, BRAF, NRAS, HRAS, ERBB2 and TP53 mutational hotspots was performed on the epithelial and stromal DNA. This information was then correlated with clinical features of the tumors.
2015-03-01 | E-GEOD-58579 | biostudies-arrayexpress
Project description:High-grade serous ovarian cancer (HGSC), the principal cause of death from gynecological malignancies in the world, has not significantly benefited from recent progress in cancer immunotherapy. While HGSC infiltration by lymphocytes correlates with superior survival, the nature of antigens that can elicit anti-HGSC immune responses is unknown. The goal of this study was to establish the global landscape of HGSC tumor-specific antigens (TSAs) using a mass spectrometry pipeline that interrogates all reading frames of all genomic regions. In 23 HGSC tumors, we identified 113 TSAs. Classic TSA discovery approaches focusing only on mutated exonic sequences would have uncovered only seven of these TSAs. Other mutated TSAs resulted from out-of-frame exonic translation or from non-exonic sequences. The most interesting group of TSAs (n = 94) derived from aberrantly expressed unmutated genomic sequences which are not expressed in normal tissues. These aberrantly expressed TSAs (aeTSAs) derived primarily from non-exonic sequences, in particular intronic (31%) and intergenic (22%). Their expression was regulated at the transcriptional level by variations in gene copy number and DNA methylation. While mutated TSAs were unique to individual tumors, aeTSAs were shared by a large proportion of HGSCs. We conclude that, in view of their number and the fact that they are shared by many tumors, aeTSAs may be the most attractive targets for HGSC immunotherapy.
2020-02-18 | PXD014062 | Pride
Project description:Lung cancer, of which more than 80% is non-small cell, is the leading cause of cancer-related death in the United States. Copy number alterations (CNAs) in lung cancer have been shown to be positionally clustered in certain genomic regions. However, it remains unclear whether genes with copy number changes are functionally clustered. Using a dense single nucleotide polymorphism array, we performed genome-wide copy number analyses of a large collection of non-small cell lung tumors (n = 301). We proposed a formal statistical test for CNAs between different groups (e.g., noninvolved lung vs. tumors, early vs. late stage tumors). We also customized the gene set enrichment analysis (GSEA) algorithm to investigate the overrepresentation of genes with CNAs in predefined biological pathways and gene sets (i.e., functional clustering). We found that CNAs events increase substantially from germline, early stage to late stage tumor. In addition to genomic position, CNAs tend to occur away from the gene locations, especially in germline, noninvolved tissue and early stage tumors. Such tendency decreases from germline to early stage and then to late stage tumors, suggesting a relaxation of selection during tumor progression. Furthermore, genes with CNAs in non-small cell lung tumors were enriched in certain gene sets and biological pathways that play crucial roles in oncogenesis and cancer progression, demonstrating the functional aspect of CNAs in the context of biological pathways that were overlooked previously. We conclude that CNAs increase with disease progression and CNAs are both positionally and functionally clustered. The potential functional capabilities acquired via CNAs may be sufficient for normal cells to transform into malignant cells. Copy number analysis was performed on 301 non-small cell lung cancer tumor samples using Affymetrix 250K Nsp GeneChip
2011-12-06 | E-GEOD-34140 | biostudies-arrayexpress
Project description:DNA-replication is a key process in life and can lead to disease when disturbed. Cell-type specific early and late replication domains have been discovered throughout genomes by analysis of DNA from populations of cells. However, cell to cell differences and the association of these differences with other cellular processes remain largely elusive. Here we demonstrate for the first time that consecutive domains of early and late DNA-replication can be detected in single S-phase cells using array comparative genomic hybridization, providing proof-of-concept for a novel tool to investigate DNA-replication genome wide at the single-cell level. Furthermore, methods to profile the genome of a single cell for DNA-copy number aberrations are revolutionizing both basic genome research and clinical genetic diagnosis. It is thus important to apprehend not only technical but also biological reasons for false positive copy number detection. None of the current single-cell copy number calling methods distinguishes between a cell in G1-, S- or G2/M-phase of the cell cycle and mostly use cells isolated randomly from populations. We demonstrate that the oscillating pattern between early and late replicating loci instigates significantly more false-positive DNA copy-number calls in a diploid cell in S-phase cells than in G1- or G2/M-phase, depending on the specific aCGH-signal normalization method used. We propose a work-flow to detect single cells in S-phase and to correct for DNA-replication bias before copy number profiling.
2013-01-08 | GSE41777 | GEO
Project description:DNA-replication is a key process in life and can lead to disease when disturbed. Cell-type specific early and late replication domains have been discovered throughout genomes by analysis of DNA from populations of cells. However, cell to cell differences and the association of these differences with other cellular processes remain largely elusive. Here we demonstrate for the first time that consecutive domains of early and late DNA-replication can be detected in single S-phase cells using array comparative genomic hybridization, providing proof-of-concept for a novel tool to investigate DNA-replication genome wide at the single-cell level. Furthermore, methods to profile the genome of a single cell for DNA-copy number aberrations are revolutionizing both basic genome research and clinical genetic diagnosis. It is thus important to apprehend not only technical but also biological reasons for false positive copy number detection. None of the current single-cell copy number calling methods distinguishes between a cell in G1-, S- or G2/M-phase of the cell cycle and mostly use cells isolated randomly from populations. We demonstrate that the oscillating pattern between early and late replicating loci instigates significantly more false-positive DNA copy-number calls in a diploid cell in S-phase cells than in G1- or G2/M-phase, depending on the specific aCGH-signal normalization method used. We propose a work-flow to detect single cells in S-phase and to correct for DNA-replication bias before copy number profiling.
2013-01-08 | GSE41776 | GEO
Project description:DNA-replication is a key process in life and can lead to disease when disturbed. Cell-type specific early and late replication domains have been discovered throughout genomes by analysis of DNA from populations of cells. However, cell to cell differences and the association of these differences with other cellular processes remain largely elusive. Here we demonstrate for the first time that consecutive domains of early and late DNA-replication can be detected in single S-phase cells using array comparative genomic hybridization, providing proof-of-concept for a novel tool to investigate DNA-replication genome wide at the single-cell level. Furthermore, methods to profile the genome of a single cell for DNA-copy number aberrations are revolutionizing both basic genome research and clinical genetic diagnosis. It is thus important to apprehend not only technical but also biological reasons for false positive copy number detection. None of the current single-cell copy number calling methods distinguishes between a cell in G1-, S- or G2/M-phase of the cell cycle and mostly use cells isolated randomly from populations. We demonstrate that the oscillating pattern between early and late replicating loci instigates significantly more false-positive DNA copy-number calls in a diploid cell in S-phase cells than in G1- or G2/M-phase, depending on the specific aCGH-signal normalization method used. We propose a work-flow to detect single cells in S-phase and to correct for DNA-replication bias before copy number profiling.
2013-01-08 | GSE38760 | GEO
Project description:DNA-replication is a key process in life and can lead to disease when disturbed. Cell-type specific early and late replication domains have been discovered throughout genomes by analysis of DNA from populations of cells. However, cell to cell differences and the association of these differences with other cellular processes remain largely elusive. Here we demonstrate for the first time that consecutive domains of early and late DNA-replication can be detected in single S-phase cells using array comparative genomic hybridization, providing proof-of-concept for a novel tool to investigate DNA-replication genome wide at the single-cell level. Furthermore, methods to profile the genome of a single cell for DNA-copy number aberrations are revolutionizing both basic genome research and clinical genetic diagnosis. It is thus important to apprehend not only technical but also biological reasons for false positive copy number detection. None of the current single-cell copy number calling methods distinguishes between a cell in G1-, S- or G2/M-phase of the cell cycle and mostly use cells isolated randomly from populations. We demonstrate that the oscillating pattern between early and late replicating loci instigates significantly more false-positive DNA copy-number calls in a diploid cell in S-phase cells than in G1- or G2/M-phase, depending on the specific aCGH-signal normalization method used. We propose a work-flow to detect single cells in S-phase and to correct for DNA-replication bias before copy number profiling.
2013-01-08 | GSE38759 | GEO