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PubMed2005

Profile of differentially expressed genes after transfer of chromosome 17 into the breast cancer cell line CAL51.

Previous studies have shown that transfer of chromosome 17 suppresses the tumorigenic phenotype of the breast cancer cell line CAL51, suggesting the presence of putative tumor suppressor genes on this chromosome. Suppression subtractive hybridization and oligonucleotide microarray analyses were performed to identify differentially expressed genes in nontumorigenic microcell hybrids, CAL/17-1 and CAL/17-3, when compared with CAL51 cells. In total, 263 differentially expressed transcripts were associated with these phenotypes. Of these, a high percentage is involved in various biological processes associated with tumorigenesis, including DNA-dependent regulation of transcription, regulation of cell cycle, signal transduction, and cell proliferation. Microarray analysis of selected chromosome 17 genes in a series of 25 human primary breast tumors showed associations with clinicopathologic parameters of the tumors. Of these genes, TOB1 (transducer of ERBB2) was selected for further expression analysis. Using RT-PCR and immunohistochemical staining of tissue microarrays, we could reveal a differential mRNA and protein expression of TOB1 in the majority of breast tumors and lymph node metastases compared with normal breast tissues, indicating a potential role of this protein in breast tumorigenesis.

Biomarkers, Tumor↗
PubMed2006

Ring chromosome 4 and Wolf-Hirschhorn syndrome (WHS) in a child with multiple anomalies.

We report on a 16-month-old male patient with ring chromosome 4 and deletion of Wolf-Hirschhorn syndrome (WHS) region with multiple congenital anomalies including unilateral cleft lip and palate, iris coloboma, microcephaly, midgut malrotation, hypospadias, and double urethral orifices. Peripheral chromosome analysis of the patient showed 46,XY,r(4)(p16.3q35) de novo. Multicolor fluorescence in situ hybridization (FISH) study was also performed and according to multicolor banding (MCB) a r(4)(::p16.3 --> q34.3 approximately 35.1::) was found in all metaphases. Subtelomeric 4p region, subtelomeric 4q region, as well as, Wolf-Hirschhorn critical region were deleted in ring chromosome 4. Genomic microarray analysis was also performed to delineate the size of deletion. Cranial magnetic resonance imaging (MRI) showed hypoplastic corpus callosum, delayed myelinization, and frontal and occipital lobe atrophies. Both maternal and paternal chromosomal analyses were normal. We compare the phenotypic appearance of our patient with the previously reported 16 cases of ring chromosome 4 in the medical literature.

Abnormalities, Multiple↗
PubMed2003

Telomeric protein distributions and remodeling through the cell cycle in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, telomeric DNA is protected by a nonnucleosomal protein complex, tethered by the protein Rap1. Rif and Sir proteins, which interact with Rap1p, are thought to have further interactions with conventional nucleosomic chromatin to create a repressive structure that protects the chromosome end. We showed by microarray analysis that Rif1p association with the chromosome ends extends to subtelomeric regions many kilobases internal to the terminal telomeric repeats and correlates strongly with the previously determined genomic footprints of Rap1p and the Sir2-4 proteins in these regions. Although the end-protection function of telomeres is essential for genomic stability, telomeric DNA must also be copied by the conventional DNA replication machinery and replenished by telomerase, suggesting that transient remodeling of the telomeric chromatin might result in distinct protein complexes at different stages of the cell cycle. Using chromatin immunoprecipitation, we monitored the association of Rap1p, Rif1p, Rif2p, and the protein component of telomerase, Est2p, with telomeric DNA through the cell cycle. We provide evidence for dynamic remodeling of these components at telomeres.

Blotting, Southern↗
PubMed2004

Gene expression microarray analysis and genome databases facilitate the characterization of a chromosome 22 derived homogeneously staining region.

Karyotype and fluorescence in situ hybridization (FISH) analyses previously identified a homogeneously staining region (HSR) derived from chromosome 22 in OV90, an epithelial ovarian cancer (EOC) cell line. Affymetrix expression microarrays in combination with the UniGene and Human Genome Browser databases were used to identify the candidate genes comprising the amplicon of the HSR, based on comparison of expression profiles of OV90, EOC cell lines lacking HSRs and primary cultures of normal ovarian surface epithelial (NOSE) cells. A group of probe sets displaying a minimum 3-fold overexpression with a high reliability score (P-call) in OV90 were identified which represented genes that mapped within a 1-2 Mb interval on chromosome 22. A large number of probe sets, some of which represent the same genes, displayed no evidence of overexpression and/or low reliability scores (A-call). An investigation of the probe set sequences with the Affymetrix and Sanger Institute Chromosome 22 Group databases revealed that some of the probe sets displaying discordant results for the same gene were complementary to intronic sequences and/or the antisense strand. Microarray results were validated by RT-PCR. Genomic analysis suggests that the HSR was derived from the amplification of a 1.1 Mb interval defined by the chromosomal map positions of ZNF74 and Hs.372662, at 22q11.21. The deduced amplicon is derived from a complex region of chromosome 22 that harbors low-copy repeats (LCRs). The amplicon contains 18 genes as likely targets for gene amplification. This study illustrates that large-scale expression microarray analysis in combination with genome databases is sufficient for deducing target genes associated with amplicons and stresses the importance of investigating probe set design before engaging in validation studies.

Cell Line, Tumor↗
PubMed2005

Lack of consensus gene expression changes associated with radiation-induced chromosomal instability.

The relatively high frequency with which ionizing radiation induces genomic instability suggests that a gene mutation occurring after irradiation is an unlikely cause of the phenotype. To search for mechanism(s) of initiation and perpetuation of this instability phenotype, gene expression profiles of clones exhibiting delayed chromosomal instability were analyzed. Microarray analysis using two pools of isogenic radiation-induced chromosomally unstable clones compared to an irradiated but chromosomally stable clone uncovered a set of 68 differentially expressed genes using two methods of analysis. Unexpectedly, all 68 genes were under-expressed relative to the chromosomally stable reference clone. Further analysis of the candidates placed the differentially expressed genes into pathways implicating differential MAP kinase signaling, ubiquitin/proteasome function, DNA repair, cell cycle control, lipid signaling, nucleotide metabolism, and other potentially disrupted pathways. Validation studies using northern and western blotting, and functional assays concluded that although differences in some of these pathways exist, no single gene or molecular pathway was found to be differentially regulated in all of the chromosomally unstable clones tested. Inferred from these data is that there are multiple potential molecular pathways and/or events that maintain the unstable phenotype, and no single expression pattern is linked to instability in the unstable clones analyzed.

Animals↗
PubMed2002

Genome scans and microarrays: converging on genes for schizophrenia?

Systematic genome-wide scans to date have shown that genes of major effect are not common causes of schizophrenia, but independent linkage studies looking for schizophrenia susceptibility genes are converging on a number of key chromosomal locations. Microarray expression analysis may identify new candidate genes and pathways, and a number of intriguing preliminary findings have already been reported.

Chromosome Mapping↗
PubMed2003

High-resolution mapping of amplifications and deletions in pediatric osteosarcoma by use of CGH analysis of cDNA microarrays.

Conventional cytogenetic and comparative genomic hybridization (CGH) studies have shown that osteosarcomas (OSs) are characterized by complex structural and numerical chromosomal alterations and gene amplification. In this study, we used high-resolution CGH to investigate recurrent patterns of genomic imbalance by use of DNA derived from nine OS tumors hybridized to a 19,200-clone cDNA microarray. In six OSs, there was copy number gain or amplification of 6p, with a minimal region of gain centering on segment 6p12.1. In seven OSs, the pattern of amplification affecting chromosome arm 8q showed high-level gains of 8q12-21.3 and 8q22-q23, with amplification of the MYC oncogene at 8q24.2. Seven OSs showed copy number gain or amplification of 17p between the loci bounded by GAS7 and PMI (17p11.2-17p12), and three of these tumors also showed small losses at 17p13, including the region containing TP53. An in silico analysis of the distribution of segmental duplications (duplicons) in this region identified a large number of tracts consisting of paralogous sequences mapping to the 17p region, encompassing the region of deletions and amplifications in OS. Interestingly, within this same region there were clusters of duplicons and several genes that are expressed during bone morphogenesis and in OS. In summary, microarray CGH analysis of the chromosomal imbalances of OS confirm the overall pattern observed by use of metaphase CGH and provides a more precise refinement of the boundaries of genomic gains and losses that characterize this tumor.

Adolescent↗
PubMed2006

Dorsal-ventral pattern of Delta trafficking is established by a Snail-Tom-Neuralized pathway.

The intracellular trafficking of the Notch ligand Delta plays an important role in the activation of the Notch pathway. We have addressed the snail-dependent regulation of Delta trafficking during the plasma membrane growth of the mesoderm in the Drosophila embryo. We show that Delta is retained in endocytic vesicles in the mesoderm but expressed on the surface of the adjacent ectoderm. This trafficking pattern requires Neuralized. We developed a protocol based on chromosomal deletion and microarray analysis that led to the identification of tom as the target of snail regulating Delta trafficking. Snail represses Tom expression in the mesoderm and thereby activates Delta trafficking. Overexpression of Tom abolishes Delta trafficking and signaling to the adjacent mesoectoderm. Loss of Tom produces mesoderm-type Delta trafficking in the entire blastoderm epithelium and an expansion of mesoectoderm gene expression. We propose that Tom antagonizes the activity of Neuralized and thus establishes a sharp mesoderm-mesoectoderm boundary of Notch signaling.

Animals↗
PubMed2006

Variation in Xi chromatin organization and correlation of the H3K27me3 chromatin territories to transcribed sequences by microarray analysis.

The heterochromatin of the inactive X chromosome (Xi) is organized into nonoverlapping bands of trimethylated lysine-9 of histone H3 (H3K9me3) and trimethylated lysine-27 of histone H3 (H3K27me3). H3K27me3 chromatin of the Xi is further characterized by ubiquitylated H2A and H4 monomethylated at lysine-20. A detailed examination of the metaphase H3K9me3 pattern revealed that banding along the chromosome arms is not a consistent feature of the Xi in all cell lines, but instead is generally restricted to the centromere and telomeres. However, H3K9me3 does form a reproducible band centered at Xq13 of the active X. In contrast, H3K27me3 banding is a feature of all Xi, but the precise combination and frequency of bands is not consistent. One notable exception is a common band at Xq22-23 that spans 12-15 Mb. The detailed examination of the chromatin territory by microarray analysis refined the H3K27me3 band as well as revealed numerous less extensive clusters of H3K27me3 signals. Furthermore, the microarray analysis indicates that H3K27me3 bands are directly correlated with gene density. The reexamination of the chromosome wide banding indicates that other major H3K27me3 bands closely align with regions of highest gene density.

Cell Line↗
PubMed2002

Molecular cytogenetic analysis of head and neck squamous cell carcinoma: By comparative genomic hybridization, spectral karyotyping, and expression array analysis.

BACKGROUND: A combination of molecular cytogenetic and expression array analysis has been performed on head and neck squamous cell carcinoma (HNSCC) of the oral cavity and supraglottis. These studies were performed to identify consensus regions of chromosomal imbalance and structural rearrangement to determine whether genes located in these genomic regions are subject to alterations in gene expression. Such combinatorial studies may help to identify recurrent patterns of altered gene expression in the context of specific chromosomal changes. METHODS: Comparative genomic hybridization (CGH) was used to identify net genomic imbalances and spectral karyotyping (SKY) to visualize the numerical and structural chromosomal changes in metaphase preparations. Expression microarray analysis of HNSCC cell lines and primary tongue tumors was also performed to identify genes that were commonly overexpressed or underexpressed compared with adjacent normal tissue. RESULTS: CGH detected gains at 3q (64%), 8q (45%) and 6q22-qter (45%) and losses at 18q22-qter (27%). SKY analysis of seven cell lines identified frequent structural rearrangement of the following chromosomal regions: 3q, 5p13-q11.2, 5q32-q34, 7p12-q11.2, 8p12-q12, 9p, 10p, 13p13-q12, 14q11.1-q11.2, 15p13-q11.2, 16p11.1-q11.1, 18q22-q23, and 22p13-q11.2. Consistent deregulation of interleukin 8, integrin alpha-6, c-MYC, epithelial discoidin domain receptor 1, and sterol regulatory element binding protein were apparent by expression analysis. Interestingly, some of these genes map to regions of genomic imbalance and chromosomal rearrangement as determined by our molecular cytogenetic analysis. CONCLUSIONS: In this small study, a combinatorial analysis using SKY, CGH, and microarray provides a model linking the changes in gene expression to changes in chromosomal dosage and structure. This approach has identified a subset of genetic changes that provide new opportunities for investigating the genetic basis of tumorigenesis in HNSCC.

Carcinoma, Squamous Cell↗
PubMed2006

Diversity arrays technology (DArT) for high-throughput profiling of the hexaploid wheat genome.

Despite a substantial investment in the development of panels of single nucleotide polymorphism (SNP) markers, the simple sequence repeat (SSR) technology with a limited multiplexing capability remains a standard, even for applications requiring whole-genome information. Diversity arrays technology (DArT) types hundreds to thousands of genomic loci in parallel, as previously demonstrated in a number diploid plant species. Here we show that DArT performs similarly well for the hexaploid genome of bread wheat (Triticum aestivum L.). The methodology previously used to generate DArT fingerprints of barley also generated a large number of high-quality markers in wheat (99.8% allele-calling concordance and approximately 95% call rate). The genetic relationships among bread wheat cultivars revealed by DArT coincided with knowledge generated with other methods, and even closely related cultivars could be distinguished. To verify the Mendelian behaviour of DArT markers, we typed a set of 90 Cranbrook x Halberd doubled haploid lines for which a framework (FW) map comprising a total of 339 SSR, restriction fragment length polymorphism (RFLP) and amplified fragment length polymorphism (AFLP) markers was available. We added an equal number of DArT markers to this data set and also incorporated 71 sequence tagged microsatellite (STM) markers. A comparison of logarithm of the odds (LOD) scores, call rates and the degree of genome coverage indicated that the quality and information content of the DArT data set was comparable to that of the combined SSR/RFLP/AFLP data set of the FW map.

Chromosomes, Plant↗
PubMed2005

The human ovarian teratocarcinoma cell line PA-1 demonstrates a single translocation: analysis with fluorescence in situ hybridization, spectral karyotyping, and bacterial artificial chromosome microarray.

Cell lines derived from tumors contain numerous chromosomal aberrations and are the focus of study in tumor evolution. The ovarian teratocarcinoma cell line PA-1 demonstrates a single chromosomal aberration: a reciprocal t(15;20)(p11.2;q11.2). A complete molecular genetic analysis was undertaken to characterize this cell line. The PA-1 cell line was studied with fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), bacterial artificial chromosome (BAC) microarray, and Western blotting. Amplification of 20q is frequently implicated in both breast and ovarian cancer; this region contains a number of oncogenes including MDM2, ZNF217, and the ovarian tumor marker WFDC2 (alias HE4). FISH revealed gene amplification of AIB1 (now known as NCOA3) but not STK15 (now known as AURKA). Immunoblot analysis demonstrated 3.6-fold overexpression of the AIB1 protein product, but no elevation of the STK15. BAC cancer gene microarray analysis showed gene amplification of > or =1.20 for five oncogenes. The presence of a consistent single change in PA-1, the t(15;20)(p11.2;q11.2), suggests that the aberration is significant with respect to the transformation status of the cell line. This translocation appears to cause overexpression of AIB1 (and perhaps other proteins), which may provide an immortalizing effect on this cell line.

Blotting, Western↗
PubMed2002

Targets of gene amplification and overexpression at 17q in gastric cancer.

DNA copy number gains and amplifications at 17q are frequent in gastriccancer, yet systematic analyses of the 17q amplicon have not been performed. In this study, we carried out a comprehensive analysis of copy number and expression levels of 636 chromosome 17-specific genes in gastric cancer by using a custom-made chromosome 17-specific cDNA microarray. Analysis of DNA copy number changes by comparative genomic hybridization on cDNA microarray revealed increased copy numbers of 11 known genes (ERBB2, TOP2A, GRB7, ACLY, PIP5K2B, MPRL45, MKP-L, LHX1, MLN51, MLN64, and RPL27) and seven expressed sequence tags (ESTs) that mapped to 17q12-q21 region. To investigate the genes transcribed at the 17q, we performed gene expression analyses on an identical cDNA microarray. Our expression analysis showed overexpression of 8 genes (ERBB2, TOP2A, GRB2, AOC3, AP2B1, KRT14, JUP, and ITGA3) and two ESTs. Of the commonly amplified transcripts, an uncharacterized EST AA552509 and the TOP2A gene were most frequently overexpressed in 82% of the samples. Additional studies will be initiated to understand the possible biological and clinical significance of these genes in gastric cancer development and progression.

Blotting, Northern↗
PubMed2004

Oligonucleotide microarray analysis of gene expression in neuroblastoma displaying loss of chromosome 11q.

A number of distinct subtypes of neuroblastoma exist with different genetic abnormalities that are predicative of outcome. Whole chromosome gains are usually associated with low stage disease and favourable outcome, whereas loss of 1p, 3p and 11q, unbalanced gain of 17q and MYCN amplification (MNA) are indicative of high stage disease and unfavourable prognosis. Although MNA and loss of 11q appear to represent two distinct genetic subtypes of advanced stage neuroblastoma, a detailed understanding of how these subtypes differ in terms of global gene expression is still lacking. We have used metaphase comparative genomic hybridization (CGH) analysis in combination with oligonucleotide technology to identify patterns of gene expression that correlate with specific genomic imbalances found in primary neuroblastic tumours and cell lines. The tumours analysed in this manner included a ganglioneuroma, along with various ganglioneuroblastoma and neuroblastoma of different stages and histopathological classifications. Oligonucleotide microarray-based gene expression profile analysis was performed with Affymetrix HU133A arrays representing approximately 14 500 unique genes. The oligonucleotide microarray results were subsequently validated by quantitative real-time PCR, immunohistochemical staining, and by comparison of specific gene expression patterns with published results. Hierarchical clustering of gene expression data distinguished tumours on the basis of stage, differentiation and genetic abnormalities. A number of genes were identified whose patterns of expression were highly correlated with 11q loss; supporting the concept that loss of 11q represents a distinct genetic subtype of neuroblastoma. The implications of these results in the process of neuroblastoma development and progression are discussed.

Biomarkers, Tumor↗
PubMed2005

Microarray analysis of gene/transcript expression in Angelman syndrome: deletion versus UPD.

Angelman syndrome (AS) is a neurodevelopmental disorder due to a functional deficit, usually a deletion, of the UBE3A gene located in the 15q11-q13 chromosome region. We report the first microarray analysis of gene expression in AS using a custom cDNA microarray to compare expression patterns from lymphoblastoid cell lines from control males and AS subjects with a 15q deletion or uniparental paternal disomy 15. Expression patterns of genes known to be biallelically expressed or paternally or maternally expressed were consistent with expectations. We detected paternal or maternal allelic bias in the expression of several genes and transcripts (e.g., GABRA5, GABRB3, WI-14946). Additionally, mechanisms controlling paternal allele expression appear to be faithfully replicated in each paternal chromosome in individuals with paternal disomy. Our results indicate that interconnected mechanisms can produce subtle and unexpected changes in gene expression that may help explain the phenotypic differences observed among the genetic subtypes of AS.

Alleles↗
PubMedDate not supplied

High resolution microarray CGH and MLPA analysis for improved genotype/phenotype evaluation of two childhood genetic disorder cases: ring chromosome 19 and partial duplication 2q.

A detailed analysis of the constitutional chromosomal changes in two pediatric patients was performed using high resolution genetic analysis techniques, microarray comparative genomic hybridization (array CGH) and multiplex ligation-dependent probe amplification (MLPA) as well as FISH. The aim was to come to a more precise characterization of the genotype/phenotype relationship. Case 1 was a girl of 25 months, showing areas of hypopigmentation along the lines of Blaschko and no other developmental abnormality. She carried a ring chromosome 19 which we found not to have resulted in loss of subtelomeric sequences, ruling out the possibility that a small subtelomeric loss was causally related to this patient's phenotype. Case 2 was a 9-year-old girl with facial anomalies and mild growth and mental retardation carrying an unidentified addition on chromosome 2p. We found that the addition was duplicated 2q35-q37.3 and that the addition was not accompanied by loss of 2pter or any other chromosomal region. Together with literature data, we hypothesize that pediatric patients with 'pure' trisomy 2q including bands 2q35-q37.1 may have a moderate clinical phenotype as opposed to patients with duplications proximal to 2q33 or patients with duplications 2q3 with accompanying distal deletion. These two examples illustrate the additional value of new, high resolution genetic analysis techniques for a better characterization of the genotype/phenotype relationship in childhood chromosomal disorders.

Child↗
PubMed2004

NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency.

complex I deficiency, the most common respiratory chain defect, is genetically heterogeneous: mutations in 8 nuclear and 7 mitochondrial DNA genes encoding complex I subunits have been described. However, these genes account for disease in only a minority of complex I-deficient patients. We investigated whether there may be an unknown common gene by performing functional complementation analysis of cell lines from 10 unrelated patients. Two of the patients were found to have mitochondrial DNA mutations. The other 8 represented 7 different (nuclear) complementation groups, all but 1 of which showed abnormalities of complex I assembly. It is thus unlikely that any one unknown gene accounts for a large proportion of complex I cases. The 2 patients sharing a nuclear complementation group had a similar abnormal complex I assembly profile and were studied further by homozygosity mapping, chromosome transfers, and microarray expression analysis. NDUFS6, a complex I subunit gene not previously associated with complex I deficiency, was grossly underexpressed in the 2 patient cell lines. Both patients had homozygous mutations in this gene, one causing a splicing abnormality and the other a large deletion. This integrated approach to gene identification offers promise for identifying other unknown causes of respiratory chain disorders.

Adolescent↗
PubMed2007

Comprehensive genomic analysis identifies MDM2 and AURKA as novel amplified genes in juvenile angiofibromas.

BACKGROUND: Frequent beta-catenin mutations have been detected in juvenile angiofibromas, but the tumor pathogenesis remains unknown. METHODS: Metaphase-comparative genomic hybridization (CGH) was used to identify chromosomal aberrations in 29 tumor specimens. Two tumors were investigated using genome DNA microarrays. RESULTS: Three hundred eleven chromosomal gains and losses were detected by metaphase-CGH. Frequent chromosomal gains were detected at 4q, 6, 12, and X, while frequent chromosomal losses affected regions of chromosomes 8, 16, 17, 22, and Y. Genome DNA microarray analysis in 2 tumors of the series confirmed chromosomal aberrations, detected by metaphase-CGH, and indicated genes such as AURKA (20q13.2) not being recognized by metaphase-CGH. CONCLUSION: Metaphase-CGH results confirmed numerous chromosomal aberrations in juvenile angiofibromas. The most frequent aberrations affected sex chromosomes. Further consensus regions of chromosomal aberrations were detected at 4q, 6, 8, 12, 16, 17, and 22. AURKA and MDM2 were identified as interesting novel amplified genes in juvenile angiofibromas.

Angiofibroma↗