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At least 163 records · Page 9Linked to original sources
PubMed2004

High-resolution global profiling of genomic alterations with long oligonucleotide microarray.

Cancer represents the phenotypic end point of multiple genetic lesions that endow cells with a full range of biological properties required for tumorigenesis. Among the hallmark features of the cancer genome are recurrent regional gains and losses that, upon detailed characterization, have provided highly productive discovery paths for new oncogenes and tumor suppressor genes. In this study, we describe the use of an oligonucleotide-based microarray platform and development of requisite assay conditions and bioinformatic mining tools that permits high-resolution genome-wide array-comparative genome hybridization profiling of human and mouse tumors. Using a commercially available 60-mer oligonucleotide microarray, we demonstrate that this platform provides sufficient sensitivity to detect single-copy difference in gene dosage of full complexity genomic DNA while offering high resolution. The commercial availability of the microarrays and associated reagents, along with the technical protocols and analytical tools described in this report, should provide investigators with the immediate capacity to perform DNA analysis of normal and diseased genomes in a global and detailed manner.

Animals↗
PubMed2002

Genome-wide profiling of gene expression in 29 normal human tissues with a cDNA microarray.

We have performed a comprehensive analysis of the expression profiles in 25 adult and 4 fetal human tissues by means of a cDNA microarray consisting of 23,040 human genes. This study revealed a number of genes that were expressed specifically in each of those tissues. Among the 29 tissues examined, 4,080 genes were highly expressed (at least a five-fold expression ratio) in one or only a few tissues and 1,163 of those were expressed exclusively (more than a ten-fold higher expression ratio) in a particular tissue. Expression of some of the genes in the latter category was confirmed by northern analysis. A hierarchical clustering analysis of gene-expression profiles in nerve tissues (adult brain, fetal brain, and spinal cord), lymphoid tissues (bone marrow, thymus, spleen, and lymph node), muscle tissues (heart and skeletal muscle), or adipose tissues (mesenteric adipose and mammary gland) identified a set of genes that were commonly expressed among related tissues. These data should provide useful information for medical research, especially for efforts to identify tissue-specific molecules as potential targets of novel drugs to treat human diseases.

Adult↗
PubMed2006

Genome wide profiling of human embryonic stem cells (hESCs), their derivatives and embryonal carcinoma cells to develop base profiles of U.S. Federal government approved hESC lines.

BACKGROUND: In order to compare the gene expression profiles of human embryonic stem cell (hESC) lines and their differentiated progeny and to monitor feeder contaminations, we have examined gene expression in seven hESC lines and human fibroblast feeder cells using Illumina bead arrays that contain probes for 24,131 transcript probes. RESULTS: A total of 48 different samples (including duplicates) grown in multiple laboratories under different conditions were analyzed and pairwise comparisons were performed in all groups. Hierarchical clustering showed that blinded duplicates were correctly identified as the closest related samples. hESC lines clustered together irrespective of the laboratory in which they were maintained. hESCs could be readily distinguished from embryoid bodies (EB) differentiated from them and the karyotypically abnormal hESC line BG01V. The embryonal carcinoma (EC) line NTera2 is a useful model for evaluating characteristics of hESCs. Expression of subsets of individual genes was validated by comparing with published databases, MPSS (Massively Parallel Signature Sequencing) libraries, and parallel analysis by microarray and RT-PCR. CONCLUSION: we show that Illumina's bead array platform is a reliable, reproducible and robust method for developing base global profiles of cells and identifying similarities and differences in large number of samples.

Carcinoma, Embryonal↗
PubMed2006

An oligonucleotide microarray for mouse imprinted genes profiling.

Genomic imprinting is an epigenetic phenomenon unique to mammals that causes some genes to be expressed according to their parental origin. It results in developmental asymmetry in the function of the parental genomes. We describe here a method for the profiling of imprinted genes based on the development of a mouse imprinting microchip containing oligonucleotides corresponding to 493 genes, including most of the known imprinted genes (IG = 63), genes involved in epigenetic processes (EPI = 15), in metabolism (= 147), in obesity (= 10) and in neurotransmission (= 256) and housekeeping reference genes (= 2). This custom oligonucleotide microarray has been constructed to make data analysis and handling more manageable than pangenomic microarrays. As a proof of concept we present the differential expression of these 493 genes in different tissues (liver, placenta, embryo) of C57BL6/J mice fed different diets. Appropriate experimental strategies and statistical tools were defined at each step of the data analysis process with regard to the different sources of constraints. Data were confirmed by expression analyses based on quantitative real-time PCR. These oligochips should make it possible to increase our understanding of the involvement of imprinted genes in the timing of expression programs, tissue by tissue, stage by stage, in response to nutrients, lifestyles and other as yet unknown critical environmental factors in a variety of physiopathological situations, and in animals of different strains, ages and sexes. The use of oligonucleotides makes it possible to expand this microchip to include the increasing number of imprinted genes discovered.

Animals↗
PubMed2004

Genome-wide profiling of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a common malignancy, the incidence of which is particularly high in some Asian countries due to the geographically linked areca quid (AQ) chewing habit. In this study, array-based comparative genomic hybridization was used to screen microdissected OSCCs for genome-wide alterations. The highest frequencies of gene gain were detected for TP63, Serpine1, FGF4/FGF3, c-Myc and DMD. The highest frequencies of deletion were detected for Caspase8 and MTAP. Gained genes, classified by hierarchical clustering, were mainly on 17q21-tel; 20q; 11q13; 3q27-29 and the X chromosome. Among these, gains of EGFR at 7p, FGF4/FGF3, CCND1 and EMS1 at 11q13, and AIB1 at 20q were significantly associated with lymph node metastasis. The genomic profiles of FHIT and EXT1 in AQ-associated and non-AQ-associated OSCCs exhibited the most prominent differences. RT-PCR confirmed the significant increase of TP63 and Serpine1 mRNA expression in OSCC relative to non-malignant matched tissue. A significant increase in Serpine1 immunoreactivity was observed from non-malignant matched tissue to OSCC. However, there was no correlation between the frequent genomic loss of Caspase 8 and a significant decrease in Caspase8 expression. These data demonstrate that genomic profiling can be useful in analysing pathogenetic events involved in the genesis or progression of OSCC.

Carcinoma, Squamous Cell↗
PubMed2005

Whole-genome expression profiling of the melanoma progression pathway reveals marked molecular differences between nevi/melanoma in situ and advanced-stage melanomas.

Over the past two decades, several known genes have been shown to govern important functions in the development of primary and metastatic melanomas. However, from this limited number of genes, it is not possible to establish detailed molecular profiles for the early and advanced stages of melanoma development. To gain insights into the genetic profile of every stage of the melanoma progression pathway, and to determine to what extent these profiles are similar or distinct, we performed whole-genome expression profiling of tissue specimens representing normal skin, benign and atypical nevi, and early and advanced-stage melanomas. The results of this study provide first-time evidence that significant molecular changes occur distinctly at the border of/transition from melanoma in situ to primary melanoma, and that genes involved in mitotic cell cycle regulation and cell proliferation constitute the two leading categories of genes associated with these changes.

Carcinoma in Situ↗
PubMed2006

Comparative genome-wide profiling of post-transplant lymphoproliferative disorders and diffuse large B-cell lymphomas.

Post-transplant lymphoproliferative disorders (PTLD) are a major complication of solid organ transplantation, representing a cause of severe morbidity and mortality. Apart from Epstein-Barr virus infection, knowledge of the pathogenesis of monoclonal PTLD is limited. Powerful analysis techniques, such as whole genomic DNA profiling (array comparative genomic hybridisation), can improve our understanding of PTLD pathogenesis. Whole genome profiling using the Affymetrix GeneChip Human Mapping 10 k 2.0 was performed on 20 PTLD cases and 25 cases of diffuse large B-cell lymphoma (DLBCL) from immunocompetent patients as a control group. Recurrent lesions were detected among all the samples. Chromosome 18q, 7q, 3q and 12 were the most common gains in the control group. Chromosomes 5p and 11p were commonly gained in PTLD-DLBCL. The latter had frequent losses of 6q, 17p, 1p and 9p. Chromosome 12p was the most frequent target of deletions among PTLD-DLBCL cases. Loss of heterozygosity (LOH) did not always match DNA loss: chromosome 10 seemed to be targeted by uniparental disomy in PTLD. Small deletions and gains, involving both known (BCL2 and PAX5) and unknown genes (ZDHHC14), were identified. These data suggest that PTLD share, at a lower frequency, common genetic aberrations with DLBCL from immunocompetent patients. The demonstration of 9p13 amplification emphasises the importance of PAX5 in PTLD. The combination of DNA copy number and LOH assessment lead to the hypothesis that uniparental disomy may be a potential mechanism in B-cell lymphomagenesis.

Chromosome Aberrations↗
PubMed1996

Restriction fragment profiles of genome segment A of infectious bursal disease virus correlate with serotype and geographical origin of avibirnaviruses.

Previous analysis of the two serotypes of infectious bursal disease virus (IBDV) have demonstrated the correlation between antigenicity and similarities of nucleotide and amino acid sequences of the VP2 coding region in genome segment A. Restriction fragment profiles of genomic segment A cDNA of five IBDV isolates (QC-2 and QT-1 of serotype 1, SK9, and Nos. 39 and 52 of serotype 2) were determined in order to establish the genetic relationship of these viruses to other avibirnaviruses. The restriction fragment profiles using three of seven restriction enzymes (SacI which cuts in the VP2 region, DraIII which cuts in the VP3 region, and EcoRI which cuts in the VP4 region) were used to place QC-2, QT-1, SK9, No. 39, and No. 52 within the phylogenetic tree among seven other avibirnaviruses of known sequence. The two IBDV serotypes corresponded to two genotypes on the basis of the presence or absence of the SacI restriction site. The serotype 1 cluster of strains was further differentiated into five minor clusters on the basis of the PstI, EcoRI, BamHI, HindIII, DraIII, and Bsu361 restriction sites, which emphasized the geographical origins of the strains. It is concluded that restriction analysis of cDNA of the whole viral genomic segment A allows differentiation of IBDV isolates on the basis of their antigenicity and geographical origin.

Australia↗
PubMed2006

Genome-wide profiling of oral squamous cell carcinoma by array-based comparative genomic hybridization.

OBJECTIVES: Array-based comparative genomic hybridization (aCGH) was used to develop a genome-wide molecular profile of oral squamous cell carcinoma (OSCC). Copy number alterations (CNAs) were identified by chromosomal region, mapped to specific genes, and compared with several previously documented CNAs associated with head and neck squamous cell carcinoma (HNSCC). The status of 512 commonly altered cancer genes was assessed and evaluated as potential correlates of tumor behavior. METHODS: Tumor tissue DNA was isolated for aCGH from 21 prospectively collected fresh-frozen OSCC specimens. aCGH was performed at 0.9-Mb resolution to identify distinct regions of genomic alteration and their associated genes. Cancer genes commonly altered were then correlated with clinicopathologic tumor data. RESULTS: Genomic regions most frequently amplified (>35%) were located on 3q, 5p, 8q, 9q, and 20q, although regions most frequently deleted (>40%) involved chromosomes 3p, 8p, 13q, and 18q. Minimal regions of CNA identified, by aCGH narrowed larger, previously documented CNAs associated with HNSCC to significantly smaller regions, yielding shorter lists of candidate genes. Cancer-related genes altered in greater than 25% OSCC samples were identified (22 amplified, 17 deleted). Several genes associated with the Fanconi anemia DNA-damage response pathway were frequently altered, including BRCA1, BRCA2, FANCD2, and FANCG. Other cancer-related genes linked to hereditary cancer syndromes include VHL, MLH1, XPC, and RB1. CONCLUSIONS: Genome-wide aCGH can be used to detect and map CNAs in OSCC tissue specimens with high resolution. These data implicate several candidate genes and gene pathways in the tumorigenesis of sporadic OSCC.

Carcinoma, Squamous Cell↗
PubMed2005

Detection of coregulation in differential gene expression profiles.

Genomics and proteomics approaches generate distinct gene expression and protein profiles, listing individual genes embedded in broad functional terms as gene ontologies. However, interpretation of gene profiles in a regulatory and functional context remains a major issue. Elucidation of regulatory mechanisms at the gene expression level via analysis of promoter regions is a prominent procedure to decipher such gene regulatory networks. We propose a novel genetic algorithm (GA) to extract joint promoter modules in a set of coexpressed genes as resulting from differential gene expression experiments. Algorithm design has focused on the following constraints: (I) identification of the major promoter modules, which are (II) characterized by a maximum number of joint motifs and (III) are found in a maximum number of coexpressed genes. The capability of the GA in detecting multiple modules was evaluated on various test data sets, analyzing the impact of the number of motifs per promoter module, the number of genes associated with a module, as well as the total number of distinct promoter modules encoded in a sequence set. In addition to the test data sets, the GA was evaluated on two biological examples, namely a muscle-specific data set and the upstream sequences of the beta-actin gene (ACTB) derived from different species, complemented by a comparison to alternative promoter module identification routines.

Actins↗
PubMed2006

Distinct array comparative genomic hybridization profiles in oral squamous cell carcinoma occurring in young patients.

BACKGROUND: Oral cancer typically affects smokers older than 50 years of age. Recently, however, a marked increase in the number of patients 40 years old and younger, many with no history of tobacco smoking, has been noted. Studies in this age group have so far been restricted to genomic areas well recognized as abnormal in typical patients with oral cancer. The aim of this study was to assess genomic aberrations in oral cancer, using comparative genomic hybridization (CGH) microarray technology, and to compare the genomic aberration profile of patients older than 40 years old with those 40 years old and younger. METHODS: Tumor samples from 20 patients with oral cancer (age range, 21-78; 10 smokers and 10 nonsmokers) were laser microdissected, and array CGH was used to identify genomic imbalances in these two cohorts. RESULTS: The older cohort showed high numbers of gains and losses in contrast to very few copy number changes in the younger nonsmoker cohort. In concurrence with the literature, tumors from the older cohort manifested deletions involving 3p and 9p21 and gains involving 3q, 5q, 7p, 8q, 11q, and 20q. The younger group, particularly the nonsmokers, showed very few changes overall, and the aberrations were not in the sites classically associated with oral cancer. Deletion of CDKN2A (p16) was completely absent in the younger group but was present in 50% of the older cohort. CONCLUSIONS: We have demonstrated that there is far less genomic instability in young nonsmokers with oral cancer than found in typical patients with oral cancer. These observations indicate that oral cancer presenting at a younger age, particularly in nonsmokers, has a genomic profile different from the classically described oral cancer.

Adult↗
PubMed2002

Analysis of altered genomic expression profiles in the senescent and diseased myocardium using cDNA microarrays.

Cardiac function deteriorates with aging or disease. Short term, any changes in heart function may be beneficial, but long term the alterations are often detrimental. At a molecular level, functional adaptations involve quantitative and qualitative changes in gene expression. Analysis of all the RNA transcripts present in a cell's population (transcriptome) offers unprecedented opportunities to map these transitions. Microarrays (chips), capable of evaluating thousands of transcripts in one assay, are ideal for transcriptome analyses. Gene expression profiling provides information about the dynamics of total genome expression in response to environmental changes and may point to candidate genes responsible for the cascade of events that result in disease or are a consequence of aging. The aim of this review is to describe how comparisons of cellular transcriptomes by cDNA array based techniques provide information about the dynamics of total gene expression, and how the results can be applied to the study of cardiovascular disease and aging.

Cardiovascular Diseases↗
PubMed2005

Microarray comparative genomic hybridization profile of a murine model for epithelial ovarian cancer reveals genomic imbalances resembling human ovarian carcinomas.

Microarray comparative genomic hybridization (mCGH) is emerging as a high-resolution technology to detect gene dosage alterations in numerous pathologies, including cancer. We optimized cDNA microarrays to identify genome-wide imbalances in spontaneously transformed mouse ovarian surface epithelial cell lines, an in vitro murine model for ovarian cancer. Amplification of chromosome 19 and a more variable gain pattern of chromosomes 15 and 5 were detected and independently validated using conventional metaphase CGH. In addition, cryptic aberrations in segments of chromosomes 4, 7, 8, 9, 11, 17, and X, allowed identification of 2 related genomic variants among six cell lines studied. Mouse-human synteny revealed an overall early transformation stage with approximately 80% conservation relative to human ovarian malignancies of epithelial origin including low malignant potential tumors, serous carcinoma, and carcinoma cell lines. Importantly, three of the cells bear gained segments 13 and 41 Mbp length of chromosomes 5 and 15, respectively, which are syntenic to human 22q11-13, 8q24 and 12p11-q24, the two latter chromosomal regions thought to define one pathway of karyotypic changes in the development of human ovarian tumors. Our findings support the utility of mouse ovarian surface epithelial (MOSE) cells in studying initiation and progression of human ovarian cancer and as a suitable model to evaluate therapeutic approaches.

Animals↗
PubMed2006

Genomic microarrays in clinical diagnosis.

PURPOSE OF REVIEW: Cytogenetic analysis has for a long time relied on chromosome banding by karyotyping for whole-genome analysis of structural and numerical chromosomal anomalies. Conceptual and technical developments in molecular cytogenetics are rapidly changing the way the human genome is being analyzed by enhancing the resolving power from the megabase to the kilobase level. This review describes the various genomic microarray approaches that have been developed for molecular cytogenetic purposes and their implementation in a routine clinical diagnostic setting. RECENT FINDINGS: Genomic microarray approaches such as array-based comparative genomic hybridization have recently been shown to identify causative submicroscopic copy number alterations in a significant proportion of patients with mental retardation. These alterations occur throughout the human genome and the majority of these alterations reported thus far are unique. Next to these causative alterations, a large number of inherited submicroscopic copy number variations without immediate clinical consequences have been detected by these methods. SUMMARY: Genome profiling by genomic microarrays is becoming an important diagnostic tool, either in addition to or replacing conventional chromosome banding, depending on the expected diagnostic yield and the costs involved.

Child, Preschool↗
PubMed2026

Age as a core disease modifier: Distinct clinical, molecular and prognostic landscapes of essential thrombocythaemia in adolescents and young adults.

Essential thrombocythaemia (ET) in adolescents and young adults (AYA, 15-39 years) is a distinct entity with an incompletely defined prognosis. In this multicentre retrospective study, 1728 ET patients from 29 centres across China were stratified into AYA (n = 328) and non-AYA (≥40 years, n = 1400) cohorts. We compared their clinical profiles, genomic landscapes, long-term outcomes and risk factors for progression to post-ET myelofibrosis (MF). AYA patients had fewer cardiovascular risks and lower thrombosis rates, but higher rates of extreme thrombocytosis. Molecularly, AYA patients were enriched for calreticulin (CALR) mutations, whereas Janus kinase 2 (JAK2) predominated in older patients. The burden of non-driver mutations (tet methylcytosine dioxygenase 2 [TET2], DNA methyltransferase 3A [DNMT3A], ASXL transcriptional regulator 1 [ASXL1], SH2‑B adaptor protein 3 [SH2B3]) was lower in AYA patients. Consequently, AYA patients achieved superior long-term outcomes across all key survival endpoints, including overall, myelofibrosis-free and leukaemia-free survival. Analysis of post-ET MF progression risks identified age-specific patterns: CALR mutations are enriched in younger patients and show an age-specific association with MF progression. AYA-ET constitutes a unique clinicomolecular subtype with a favourable prognosis, supporting age-stratified management. The enrichment of CALR mutations and their specific link to MF progression in young patients underscore the urgent need for targeted therapies against CALR-mutant clones.

adolescents and young adults (AYA)↗
PubMed2004

Molecular tumor profiling: translating genomic insights into clinical advances.

Molecular profiling of the transcripts or proteins within an individual tumor may in future provide important prognostic and therapeutic clinical information both for the affected individual and for their extended family, but for the time being traditional genetics and pathology retain their place in the clinic.

Breast Neoplasms↗
PubMed2004

Genome signatures of colon carcinoma cell lines.

In cancer biology, cell lines are often used instead of primary tumors because of their widespread availability and close reflection of the in vivo state. Cancer is a genetic disease, commonly caused by small- and large-scale DNA rearrangements. Therefore, it is essential to know the genomic profiles of tumor cell lines to enable their correct and efficient use as experimental tools. Here, we present a comprehensive study of the genomic profiles of 20 colon cancer cell lines combining conventional karyotyping (G-banding), comparative genomic hybridization (CGH), and multicolor fluorescence in situ hybridization (M-FISH). Major differences between the microsatellite instability (MSI) and chromosome instability (CIN) cell lines are shown; the CIN cell lines exhibited complex karyotypes involving many chromosomes (mean: 8.5 copy number changes), whereas the MSI cell lines showed considerably fewer aberrations (mean: 2.6). The 3 techniques complement each other to provide a detailed picture of the numerical and structural chromosomal changes that characterize cancer cells. Therefore, 7 of the cell lines (Colo320, EB, Fri, IS2, IS3, SW480, and V9P) are here completely karyotyped for the first time and, among these, 5 have not previously been cytogenetically described. By hierarchical cluster analysis, we show that the cell lines are representative models for primary carcinomas at the genome level. We also present the genomic profiles of an experimental model for tumor progression, including 3 cell lines (IS1, IS2, and IS3) established from a primary carcinoma, its corresponding liver- and peritoneal metastasis from the same patient. To address the question of clonality, we compared the genome of 3 common cell lines grown in 2 laboratories. Finally, we compared all our results with previously published CGH data and karyotypes of colorectal cell lines. In conclusion, the large variation in genetic complexity of the cell lines highlights the importance of a comprehensive reference of genomic profiles for investigators engaged in functional studies using these research tools.

Cell Line, Tumor↗
PubMed2003

Analysis of the mutational effects of the COP/DET/FUS loci on genome expression profiles reveals their overlapping yet not identical roles in regulating Arabidopsis seedling development.

Microarray gene expression profiling was used to examine the role of pleiotropic COP/DET/FUS loci as well as other partially photomorphogenic loci during Arabidopsis seedling development and genome expression regulation. Four types of lethal, pleiotropic cop/det/fus mutants exhibit qualitatively similar gene expression profiles, yet each has specific differences. Mutations in COP1 and DET1 show the most similar genome expression profiles, while the mutations in the COP9 signalosome (CSN) and COP10 exhibit increasingly diverged genome expression profiles in both darkness and light. The genome expression profiles of the viable mutants of COP1 and DET1 in darkness mimic those of the physiological light-regulated genome expression profiles, whereas the genome expression profiles of representative lethal mutants belong to another clade and significantly diverge from the normal light control of genome expression. Instead, these lethal pleiotropic mutants show genome expression profiles similar to those from seedlings growth under high light intensity stress. Distinct lethal pleiotropic cop/det/fus mutants also result in distinct expression profiles in the small portion of genes examined and exhibit similar relatedness in both light and darkness. The partial cop/det/fus mutants affected expression of both light regulated and non-light regulated genes. Our results suggest that pleiotropic COP/DET/FUS loci control is largely overlapping but also has separable roles in plant development. The partially photomorphogenic loci regulate a subset of photomorphogenic responses as well as other non-light regulated processes.

Arabidopsis↗