Integrated genomic and gene expression profiling identifies two major gene/genomic circuits operating in urothelial carcinoma (gene expression)
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: David Lindgren
PROVIDER: E-GEOD-32548 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma.
Lindgren David D Sjödahl Gottfrid G Lauss Martin M Staaf Johan J Chebil Gunilla G Lövgren Kristina K Gudjonsson Sigurdur S Liedberg Fredrik F Patschan Oliver O Månsson Wiking W Fernö Mårten M Höglund Mattias M
PloS one 20120607 6
Similar to other malignancies, urothelial carcinoma (UC) is characterized by specific recurrent chromosomal aberrations and gene mutations. However, the interconnection between specific genomic alterations, and how patterns of chromosomal alterations adhere to different molecular subgroups of UC, is less clear. We applied tiling resolution array CGH to 146 cases of UC and identified a number of regions harboring recurrent focal genomic amplifications and deletions. Several potential oncogenes we ...[more]
Similar Datasets
Project description:This SuperSeries is composed of the following subset Series: GSE32535: Integrated genomic and gene expression profiling identifies two major gene/genomic circuits operating in urothelial carcinoma (genomic) GSE32548: Integrated genomic and gene expression profiling identifies two major gene/genomic circuits operating in urothelial carcinoma (gene expression) Refer to individual Series
2012-06-17 | E-GEOD-32549 | biostudies-arrayexpress
Project description:We assessed DNA methylation and copy number status of 27,000 CpGs in 149 urothelial carcinomas and integrated the findings with gene expression and mutation data. Methylation was associated with gene expression for 1,332 CpGs, of which 26% showed positive correlation with expression, i.e., high methylation and high gene expression levels. These positively correlated CpGs were part of specific transcription factor binding sites, such as sites for MYC and CREBP1, or located in gene bodies. Furthermore, we found genes with copy number gains, low expression and high methylation levels, revealing an association between methylation and copy number levels. This phenomenon was typically observed for developmental genes, such as HOX genes and tumor suppressor genes. In contrast, we also identified genes with copy number gains, high expression and low methylation levels. This was for instance observed for some keratin genes. Tumor cases could be grouped into four subgroups, termed epitypes, by their DNA methylation profiles. One epitype was influenced by the presence of infiltrating immune cells, two epitypes were mainly composed of non-muscle invasive tumors, and the remaining epitype of muscle invasive tumors. The polycomb complex protein EZH2 that blocks differentiation in embryonic stem cells showed increased expression both at the mRNA and protein levels in the muscle invasive epitype, together with methylation of polycomb target genes and HOX genes. Our data highlights HOX gene silencing and EZH2 expression as mechanisms to promote a more undifferentiated and aggressive state in UC. The study was conducted on genomic DNA from 150 primary fresh-frozen urothelial carcinoma tumors selected to have equal representation of stages Ta, T1 and T2>. The design also included four fully methylated and four unmethylated hybridization controls as well as 7 Normal urothelium samples. One tumor sample (UC_0556_1) was included as a technical replicate in each of four bisulfite treatment batches. The samples were bisulfite treated and hybridized to Illumina Human Methylation27 Bead Chip arrays according to manufacturers instructions at the SCIBLU Genomics Centre at Lund University, Sweden. Note: Illumina methylation data set comprises total of 168 samples (raw data), but 156 samples (processed data), derived from primary urothelial carcinoma samples. See README.txt for details of the 12 samples not included in the final, processed data.
2012-08-31 | E-GEOD-33510 | biostudies-arrayexpress
Project description:Background: Previous array CGH analyses have revealed several recurring genomic alterations in urothelial carcinoma. The most common genomic amplifications occur at 6p22 and 1q21-24. The main target gene at 6p22 is believed to be E2F3. This gene is frequently co-amplified with CDKAL1 and SOX4 and there are reports on 6p22 amplifications that do not include the E2F3 locus. Previous array CGH analyses have indicated multiple possible target regions at 1q21-24. However, due to complex rearrangements it has been difficult to identify specific 1q21-24 target regions and target genes. Results: We show that the most commonly amplified gene at 6p22 is SOX4 and that SOX4 can be amplified and over expressed without E2F3 or CDKAL1 being included in the amplicon. Hence, our data point to SOX4 as an auxiliary amplification target at 6p22. We further show that at least three amplified regions are observed at 1q21-24. Copy number data, combined with gene expression data, highlighted BCL9 and CHD1L as possible targets in the most proximal region and MCL1, SETDB1, and HIF1B as targets in the middle region, whereas no obvious gene targets could be determined in the most distal amplicon. We also highlight the enrichment of G4 quadruplex sequence motifs and the high number of intraregional sequence duplications, both known to contribute to genomic instability, as prominent features of the 1q21-24 region. Conclusions: Our detailed analyses of the 6p22 amplicon in urothelial carcinomas suggest SOX4 as an auxiliary target gene for amplification. We further demonstrate three separate target regions for amplification at 1q21-24 and identified BCL9, CHD1L, MCL1, SETDB1, and HIF1B as likely target genes within these regions. The study was conducted on genomic DNA from 68 primary fresh-frozen urothelial carcinoma tumors analysed using a Agilent SurePrint G3 4x180k Custom CGH Microarray Platform (028432). Samples were selected based on the presence of copy number alterations observed on lower resolution genomic data (32K BAC array). The majority of the BAC data is publicly available in GEO submissions GSE32535 and GSE19915. CN profiles for a minority of samples were derived from Illumina Methylation27k arrays according to Lauss et al 2012 [PMID: 22705924] and can be recreated from the data deposited in GSE33510 (derived CN data). Sample names are the same between all studies. This dataset also partly overlaps with Series GSE32894 (gene expression data). Names of the overlapping sample names are the same and indicated in the description field. Data from GSE32894 was used to calculate correlations between CN and gene expression.
2013-08-30 | E-GEOD-40938 | biostudies-arrayexpress
Project description:The adult kidney has a remarkable capacity for self-renewal upon damage. Whether this regeneration is mediated by dedifferentiating surviving cells or as recently suggested by stem cells has not been unequivocally settled. The stem cell concept is however hampered by lack of consensus regarding the histological localization of and defining markers for these cells. Here, we demonstrate that aldehyde dehydrogenase (ALDH) activity may be used for isolation of cells with progenitor-like characteristics from adult human renal cortical tissue. Gene expression profiling of the isolated ALDHhigh and ALDHlow cell fractions followed by immunohistochemical interrogation of renal tissues enabled us to delineate a tentative progenitor cell population with a scattered distribution in the epithelial layer of the proximal tubules (PT). The cells differed from the surrounding cells by expression of CD133, CD24, vimentin, KRT7, KRT19, and BCL2, and were negative for PT-specific markers. Based on functional and bioinformatic analyses as well as an immunophenotypical resemblance to cells of regenerating tubules we suggest that these cells are endowed with a more robust phenotype, allowing increased resistance to acute renal injury, enabling rapid repopulation of the tubules. The rare intratubular cells also displayed marked transcriptional and immunophenotypical similarities to that of cortical adenomas and papillary renal cell carcinomas, indicating that these renal neoplasms arise through oncogenic transformation of this subset of PT cells. Total RNA extracted from three pairs of ALDH-high and ALDH-low cell fractions were hybridized to Illumina humanHT-12 v3.0 Expression BeadChips (Illumina Inc) at the SCIBLU Genomics Centre at Lund University Sweden (http://www.lth.se/sciblu).
2010-11-01 | E-GEOD-23911 | biostudies-arrayexpress
Project description:Genomic and gene expression profiling identifies two major gene/genomic circuits operating in urothelial carcinoma 146 primary bladder cancer tumor samples were analyzed on BAC array containing ~32 000 BAC clones. Arrays were produced at the Swegene Centre for Integrative Biology at Lund University (SCIBLU).
2012-06-17 | E-GEOD-32535 | biostudies-arrayexpress
Project description:Even though urothelial cancer (UC) is the fourth common tumor type among males, progress in treatment development has been deficient. Pathological assessment provides the urologists with only a broad classification, complicated by frequent disagreement among pathologist and the co-existence of different grading systems. Consequently, there is a great need for an objective, reproducible and biologically relevant classification system to make treatment more efficient. In the present investigation we present a molecular taxonomy for UC stratification based on integrated genomics. We used gene expression profiles from 308 UC to define seven molecular subtypes using step-by-step partitions and a bootstrap approach. Results were validated in three independent and publically available data sets. The subtypes differ significantly with respect to expression of cell cycle genes, of receptor tyrosine kinases particularity FGFR3, ERBB2 (HER2), and EGFR, of an FGFR3 associated gene expression signature, of cytokaratins, and of cell adhesion genes. The subtypes also differ significantly with respect to FGFR3, PIK3CA, and TP53 mutations. The expression of key proteins was validated by IHC on TMA. A further inspection indicated that the subtypes could be reduced to four major types of UC; Urobasal/D-driven, Genomically unstable/E-driven, Evolved urobasal, and Basal/SCC like, with characteristic and highly divergent molecular phenotypes. We show that the molecular subtypes cut across pathological classification and that tumors classified as one subtype maintain their characteristic molecular phenotype irrespective of pathological stage and grade. Available data from the Drugbank database and the Cochrane central registry of controlled trials indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathological classification. The presented molecular taxonomy stratifies UC into subtypes with distinct molecular phenotypes and biological properties. We anticipate that the molecular taxonomy will be a useful tool in future clinical investigations. Total RNA from fresh-frozen resection samples of 308 urothelial carcinomas was hybridized to the Illumina HumanHT-12 V3.0 expression beadchip arrays (Illumina Inc) at the SCIBLU Genomics Centre at Lund University Sweden (http://www.lth.se/sciblu). Supplementary files: GSE32894_non-normalized_308UCsamples.txt file = Raw intensity values for 308 UC (urothelial tumor) samples subjected only to background correction. GSE32894_reps_normals_preprocess*.txt files = Descriptive details and non-normalized data for technical replicates and normal samples that were used only in the preprocessing of the data. This dataset partly overlaps with Series GSE32549. Names of the overlapping sample names are the same, but the title of each sample is unique to the hybridization.
2012-05-23 | E-GEOD-32894 | biostudies-arrayexpress
Project description:Background Urothelial carcinoma of the bladder (UC) is a common malignancy. Although extensive transcriptome analysis has provided insights into the gene expression patterns of this tumor type, the mechanistic underpinnings of differential methylation remain poorly understood. Multi-level genomic data may be used to profile the regulatory potential and landscape of differential methylation in cancer and gain understanding of the processes underlying epigenetic and phenotypic characteristics of tumors. Methods We perform genome-wide DNA methylation profiling of 98 gene-expression subtyped tumors to identify between-tumor differentially methylated regions (DMRs). We integrate multi-level publically available genomic data generated by the ENCODE consortium to characterize the regulatory potential of UC DMRs. Results We identify 5,453 between-tumor DMRs and derive four DNA methylation subgroups of UC with distinct associations to clinicopathological features and gene expression subtypes. We characterize three distinct patterns of differential methylation and use ENCODE data to show that tumor subgroup-defining DMRs display differential chromatin state, and regulatory factor binding preferences. Finally, we characterize an epigenetic switch involving the HOXA-genes with associations to tumor differentiation states and patient prognosis. Conclusions Genome-wide DMR methylation patterns are reflected in the gene expression subtypes of UC. UC DMRs display three distinct methylation patterns, each associated with intrinsic features of the genome and differential regulatory factor binding preferences. Epigenetic inactivation of HOX-genes correlates with tumor differentiation states and may present an actionable epigenetic alteration in UC. MeDIP hybridizations on 98 human urothelial carcinoma samples and 4 normal urothelium samples on Nimblegen 3x720K RefSeq Promoter and CGI aCGH arrays.
2015-05-28 | E-GEOD-58256 | biostudies-arrayexpress
Project description:Breast cancer is a profoundly heterogeneous disease with respect to biological and clinical behavior. Gene expression profiling has been used to dissect this complexity and stratify tumors into intrinsic gene expression subtypes associated with distinct biology, patient outcome and different genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes. We applied global DNA copy number and gene expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy number aberrations and genomic subgroups of breast cancer. We identified 31 genomic regions that were highly amplified in >1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions (66 and 67 with DNA copy number gain and loss, respectively) revealed six genomic subtypes, termed: 17q12, basal-complex, luminal-simple, luminal-complex, amplifier and mixed subtype. Four of them had striking similarity to intrinsic gene expression subtypes and showed association to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having better prognosis while the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene expression subtypes, the former being enriched for 8p12-amplified cases while the mixed subtype included many tumors with predominantly DNA copy number losses and poor prognosis. Genomic profiling of 359 breast tumors using tiling BAC aCGH. A number of cases were hybridized as replicates or replicate as dye-swaps. Gene expression profiling of 359 breast tumors using 55K oligonucleotide microarrays.
2010-06-23 | E-GEOD-22133 | biostudies-arrayexpress
Project description:Plasma proteome is the ultimate target for the biomarker discovery. It stores an endless amount of information on the pathophysiological status of a living organism, which however is still difficult to comprehensively access. The high structural complexity of the plasma proteome can be addressed by using a system-wide and unbiased tool such as mass spectrometry (LC-MS/MS) or highly sensitive targeted immunoassays as Olink Proximity Extension Assays. We have tested the performance of LC-MS/MS in data –dependent and -independent acquisition modes and Olink PEA to measure circulating plasma proteins in 173 human plasma samples from a southern Germany population-cohort. More than 300 proteins were measured by both LC-MS/MS approaches, mainly including high abundance functional plasma proteins. By using the Olink PEA technology we measured 728 plasma proteins, covering a broad dynamic range with high sensitivity down to pg/ml levels. We found 35 overlapping proteins in all three analytical platforms, predominantly secreted and highly abundant in plasma. The complementarity of the platforms was assessed by veryfing the reproducibility of data distributions, statistical correlation of measurements and gender-based differential expression analysis. Our work highlights the limitations and the advantages of both targeted and untargeted approaches and prove their complementarity. We demostrated that by combining the results of the three platforms we gain in depth proteome coverage as well as biological insights.
2022-03-10 | PXD020261 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE12439: Genomic profiling of chondrosarcoma: implications for the distinction between central and peripheral tumors GSE12475: Genomic profiling of chondrosarcoma: implications for the distinction between central and peripheral tumors Refer to individual Series
2009-04-01 | E-GEOD-12532 | biostudies-arrayexpress