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PubMed2006

High resolution analysis of genomic aberrations by metaphase and array comparative genomic hybridization identifies candidate tumour genes in lung cancer cell lines.

Tumours develop from clonally expanded population of cells harbouring aberrations of oncogenes and tumour suppressor genes. In this study, metaphase and array comparative genomic hybridization showed good correlation of aberration profiles in lung adenocarcinoma cell lines from patients with different tobacco exposure. Recurrent DNA gains were found at chromosomes 1, 7, 8, 17, 20, and deletions at 1, 3, 8, 9, 10, 12, 17, 18, 19. Candidate tumour loci and encompassed genes at 7p21 (AGR2), 8q21(TPD52), 20q13 (ZNF217, WFDC2, EEF1A2) and 10p15 (KLF6) were analyzed by dual colour FISH for genomic changes and quantitative PCR for expression changes. Results indicated that EEF1A2 and KLF6 were strong candidates of oncogene and tumour suppressor genes, respectively. This study illustrates, a practical strategy for identifying candidate cancer genes from microarray data.

Adenocarcinoma↗
PubMed2002

Mapping and analysis of quantitative trait loci in experimental populations.

Simple statistical methods for the study of quantitative trait loci (QTL), such as analysis of variance, have given way to methods that involve several markers and high-resolution genetic maps. As a result, the mapping community has been provided with statistical and computational tools that have much greater power than ever before for studying and locating multiple and interacting QTL. Apart from their immediate practical applications, the lessons learnt from this evolution of QTL methodology might also be generally relevant to other types of functional genomics approach that are aimed at the dissection of complex phenotypes, such as microarray assessment of gene expression.

Algorithms↗
PubMed2004

The CLCA gene locus as a modulator of the gastrointestinal basic defect in cystic fibrosis.

To determine whether the CLCA gene family of calcium-activated chloride channels is a modulator of the basic defect of cystic fibrosis (CF), an association study was performed with polymorphic microsatellite markers covering a 40-Mbp region spanning the CLCA gene locus on human chromosome 1p in CF patients displaying CF transmembrane conductance regulator (CFTR)-independent residual chloride conductance in gastrointestinal epithelia. Statistically significant association of the electrophysiological phenotype with the allele distribution of markers 5' of and within the CLCA locus was observed. Transmission disequilibrium and the significance of the association decreased within the locus from hCLCA2 towards hCLCA4. Expression of hCLCA1 and hCLCA4 in human rectal mucosa was proven by microarray analysis. The CLCA gene region was identified to encode mediators of DIDS-sensitive anion conductance in the human gastrointestinal tract that modulate the CF basic defect.

Alleles↗
PubMedDate not supplied

Targeting topoisomerase IIa in endometrial adenocarcinoma: a combined chromogenic in situ hybridization and immunohistochemistry study based on tissue microarrays.

Topoisomerase IIa is a nucleic enzyme that affects the topological structure of DNA and also is a target for chemotherapy (ie, anthracyclines). In this study, we coevaluated its protein expression with chromosome 17 and gene status. Using tissue microarrays, 40 cases of sporadic, primary endometrial adenocarcinomas, 5 cases of atypical hyperplasia, and 5 cases of benign hyperplasia were obtained and reembedded into two paraffin blocks with a core diameter of 1 mm. Immunohistochemistry combined with chromogenic in situ hybridization was performed in 2 and 5 microm sections, respectively. Finally using a semiautomated Image Analysis System, we evaluated the levels of Nuclear labeling index of topoisomerase IIa expression. Statistical analysis was performed by SPSS version 11.0 software. The results indicate that chromosome 17 instability (aneuploidy in 7/40 cases) and Topo IIa gene deregulation (amplification in 3/40 and deletion in 1/40 cases) are significant genetic events correlated with biologic behavior in endometrial adenocarcinoma. Because protein overexpression was observed in a significant proportion of the tumors (18/40), detection of the specific gene deregulation mechanism is a crucial process for application of targeted chemotherapies, which are characterized by different levels of cardiotoxicity and other serious effects.

Adenocarcinoma↗
PubMed2006

Mapping novel traits by array-assisted bulk segregant analysis in Saccharomyces cerevisiae.

We demonstrate a new method, microarray-assisted bulk segregant analysis, for mapping traits in yeast by genotyping pooled segregants. We apply a probabilistic model to the progeny of a single cross and as little as two microarray hybridizations to reliably map an auxotrophic marker, a Mendelian trait, and a major-effect quantitative trait locus.

Chromosome Mapping↗
PubMed2006

A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene.

Stickler syndrome is characterized by ophthalmic, articular, orofacial, and auditory manifestations. It has an autosomal dominant inheritance pattern and is caused by mutations in COL2A1, COL11A1, and COL11A2. We describe a family of Moroccan origin that consists of four children with Stickler syndrome, six unaffected children, and two unaffected parents who are distant relatives (fifth degree). All family members were clinically investigated for ear, nose, and throat; ophthalmologic; and radiological abnormalities. Four children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. We considered the COL9A1 gene, located on chromosome 6q13, to be a candidate gene on the basis of the structural association with collagen types II and XI and because of the high expression in the human inner ear indicated by cDNA microarray. Mutation analysis of the coding region of the COL9A1 gene showed a homozygous R295X mutation in the four affected children. The parents and four unaffected children were heterozygous carriers of the R295X mutation. Two unaffected children were homozygous for the wild-type allele. None of the family members except the homozygous R295X carriers had any signs of Stickler syndrome. Therefore, COL9A1 is the fourth identified gene that can cause Stickler syndrome. In contrast to the three previously reported Stickler syndrome-causing genes, this gene causes a form of Stickler syndrome with an autosomal recessive inheritance pattern. This finding will have a major impact on the genetic counseling of patients with Stickler syndrome and on the understanding of the pathophysiology of collagens. Mutation analysis of this gene is recommended in patients with Stickler syndrome with possible autosomal recessive inheritance.

Child↗
PubMed2005

Characterization of the pheromone response of the Enterococcus faecalis conjugative plasmid pCF10: complete sequence and comparative analysis of the transcriptional and phenotypic responses of pCF10-containing cells to pheromone induction.

The sex pheromone plasmids in Enterococcus faecalis are one of the most efficient conjugative plasmid transfer systems known in bacteria. Plasmid transfer rates can reach or exceed 10(-1) transconjugants per donor in vivo and under laboratory conditions. We report the completion of the DNA sequence of plasmid pCF10 and the analysis of the transcription profile of plasmid genes, relative to conjugative transfer ability following pheromone induction. These experiments employed a mini-microarray containing all 57 open reading frames of pCF10 and a set of selected chromosomal genes. A clear peak of transcription activity was observed 30 to 60 min after pheromone addition, with transcription subsiding 2 h after pheromone induction. The transcript activity correlated with the ability of donor cells to transfer pCF10 to recipient cells. Remarkably, aggregation substance (Asc10, encoded by the prgB gene) was present on the cell surface for a long period of time after pheromone-induced transcription of prgB and plasmid transfer ability had ceased. This observation could have relevance for the virulence of E. faecalis.

Chromosome Mapping↗
PubMed2006

E Proteins and Id2 converge on p57Kip2 to regulate cell cycle in neural cells.

A precise balance between proliferation and differentiation must be maintained during neural development to obtain the correct proportion of differentiated cell types in the adult nervous system. The basic helix-loop-helix (bHLH) transcription factors known as E proteins and their natural inhibitors, the Id proteins, control the timing of differentiation and terminal exit from the cell cycle. Here we show that progression into S phase of human neuroblastoma cells is prevented by E proteins and promoted by Id2. Cyclin-dependent kinase inhibitors (CKI) have been identified as key effectors of cell cycle arrest in differentiating cells. However, p57Kip2 is the only CKI that is absolutely required for normal development. Through the use of global gene expression analysis in neuroblastoma cells engineered to acutely express the E protein E47 and Id2, we find that p57Kip2 is a target of E47. Consistent with the role of Id proteins, Id2 prevents activation of p57Kip2 expression, and the retinoblastoma tumor suppressor protein, a known Id2 inhibitor, counters this activity. The strong E47-mediated inhibition of entry into S phase is entirely reversed in cells in which expression of p57Kip2 is silenced by RNA interference. During brain development, expression of p57Kip2 is opposite that of Id2. Our findings identify p57Kip2 as a functionally relevant target recruited by bHLH transcription factors to induce cell cycle arrest in developing neuroblasts and suggest that deregulated expression of Id proteins may be an epigenetic mechanism to silence expression of this CKI in neural tumors.

Adenoviridae↗
PubMed2002

Mapping of early firing origins on a replication profile of budding yeast.

BACKGROUND: Understanding of the firing time determination of replication origins in the entire genome will require a genome-wide survey of replication origins and their mapping on chromosomes. A microarray technology was applied to obtain a genome-wide profile of DNA replication and to classify early firing origins. RESULTS: A total of 260 potential replication origins (PROs) were identified in the entire budding yeast genome: 247 as defined peaks on the replication profile and 13 as regions located in the chromosomal termini. Based on the firing time, the 247 PROs were classified into 143 early PROs and 104 late PROs, that were not randomly distributed on chromosomes but formed separated clusters. Most of the early PROs were found to fire in the presence of hydroxyurea, indicating that they were free from the control of the intra-S-checkpoint mediated by Mec1 and Rad53. CONCLUSIONS: The monitoring method of DNA replication and the analysis method of microarray data used in this study proved powerful for obtaining a genome-wide view of the initiation and progression of DNA replication.

Base Sequence↗
PubMed2002

Molecular genetics of schizophrenia: past, present and future.

Schizophrenia is a severe neuropsychiatric disorder with a polygenic mode of inheritance which is also governed by non-genetic factors. Candidate genes identified on the basis of biochemical and pharmacological evidence are being tested for linkage and association studies. Neurotransmitters, especially dopamine and serotonin have been widely implicated in its etiology. Genome scan of all human chromosomes with closely spaced polymorphic markers is being used for linkage studies. The completion and availability of the first draft of Human Genome Sequence has provided a treasure-trove that can be utilized to gain insight into the so far inaccessible regions of the human genome. Significant technological advances for identification of single nucleo-tide polymorphisms (SNPs) and use of microarrays have further strengthened research methodologies for genetic analysis of complex traits. In this review, we summarize the evolution of schizophrenia genetics from the past to the present, current trends and future direction of research.

Anticipation, Genetic↗
PubMed2005

THY1 is a candidate tumour suppressor gene with decreased expression in metastatic nasopharyngeal carcinoma.

Using oligonucleotide microarray analysis, THY1, mapping close to a previously defined 11q22-23 nasopharyngeal carcinoma (NPC) critical region was identified as showing consistent downregulated expression in the tumour segregants, as compared to their parental tumour-suppressing microcell hybrids (MCHs). Gene expression and protein analyses show that THY1 was not expressed in the NPC HONE1 recipient cells, tumour segregants, and other NPC cell lines; THY1 was exclusively expressed in the non-tumourigenic MCHs. The mechanism of THY1 gene inactivation in these cell lines was attributed to hypermethylation. Clinical study showed that in 65% of NPC specimens there was either downregulation or loss of THY1 gene expression. Using a tissue microarray and immunohistochemical staining, 44% of the NPC cases showed downregulated expression of THY1 and 9% lost THY1 expression. The frequency of THY1 downregulated expression in lymph node metastatic NPC was 63%, which was significantly higher than in the primary tumour (33%). After transfection of THY1 gene into HONE1 cells, a dramatic reduction of colony formation ability was observed. These findings suggest that THY1 is a good candidate tumour suppressor gene in NPC, which is significantly associated with lymph node metastases.

Carcinoma↗
PubMed2004

Use of segment-based microarray in the analysis of global gene expression in response to various environmental stresses in the cyanobacterium Anabaena sp. PCC 7120.

We prepared microarrays that contain genomic sequences of a heterocyst-forming filamentous cyanobacterium Anabaena sp. PCC 7120. The complete genome of this cyanobacterium codes for about 5,368 protein-coding genes in the main chromosome of 6.4 Mbp. In total, 2,407 DNA segments were selected from the sequencing clones, and amplified by PCR, then spotted on glass slides in duplicate. These microarrays differ from the widely used commercial or custom-made ones for other microorganisms in that each DNA segment was 3-4 kbp long, and contained about 3-4 predicted genes on average. This feature, however, did not decrease the usefulness of the microarrays, since we were able to detect a number of potentially novel genes that are induced in response to nitrogen deprivation, low temperature and drought. In addition, we found some genomic regions in which dozens of contiguous genes are simultaneously regulated. These results suggest that these segment-based microarrays are useful especially for such large genomes as Anabaena, for which the number of genes exceeds either technical or practical limitations.

Anabaena↗
PubMed2007

Allelic loss in a minimal region on chromosome 16q24 is associated with vitreous seeding of retinoblastoma.

In addition to RB1 gene mutations, retinoblastomas frequently show gains of 1q and 6p and losses of 16q. To identify suppressor genes on 16q, we analyzed 22 short tandem repeat loci in 58 patients with known RB1 mutations. A subset of tumors was also investigated by conventional and matrix comparative genomic hybridization. In 40 of 58 (69%) tumors, we found no loss of heterozygosity (LOH) at any 16q marker. LOH was detected in 18 of 58 (31%) tumors, including five with allelic imbalance at some markers. In one tumor LOH was only observed at 16q24. As the parental origin of allele loss was unbiased, an imprinted locus is unlikely to be involved. Analysis of gene expression by microarray hybridization and quantitative RT real-time PCR did not identify a candidate suppressor in 16q24. Cadherin 13 (CDH13), CBFA2T3, and WFDC1, which are candidate suppressors in other tumor entities with 16q24 loss, did not show loss of expression. In addition, mutation and methylation analysis showed no somatic alteration of CDH13. Results in all tumors with chromosome 16 alterations define a single minimal deleted region of 5.7 Mb in the telomeric part of 16q24 with the centromeric boundary defined by retention of heterozygosity for a single nucleotide variant in exon 10 of CDH13 (Mb 82.7). Interestingly, clinical presentation of tumors with and without 16q alterations was distinct. Specifically, almost all retinoblastomas with 16q24 loss showed diffuse intraocular seeding. This suggests that genetic alterations in the minimal deleted region are associated with impaired cell-to-cell adhesion.

Cadherins↗
PubMed2003

Obesity and diabetes gene discovery approaches.

New treatments are currently required for the common metabolic diseases obesity and type 2 diabetes. The identification of physiological and biochemical factors that underlie the metabolic disturbances observed in obesity and type 2 diabetes is a key step in developing better therapeutic outcomes. The discovery of new genes and pathways involved in the pathogenesis of these diseases is critical to this process, however identification of genes that contribute to the risk of developing these diseases represents a significant challenge as obesity and type 2 diabetes are complex diseases with many genetic and environmental causes. A number of diverse approaches have been used to discover and validate potential new targets for obesity and diabetes. To date, DNA-based approaches using candidate gene and genome-wide linkage analysis have had limited success in identifying genomic regions or genes involved in the development of these diseases. Recent advances in the ability to evaluate linkage analysis data from large family pedigrees using variance components based linkage analysis show great promise in robustly identifying genomic regions associated with the development of obesity and diabetes. RNA-based technologies such as cDNA microarrays have identified many genes differentially expressed in tissues of healthy and diseased subjects. Using a combined approach, we are endeavouring to focus attention on differentially expressed genes located in chromosomal regions previously linked with obesity and/or diabetes. Using this strategy, we have identified Beacon as a potential new target for obesity and diabetes.

Amino Acid Sequence↗
PubMed2006

Y chromosome loss and other genomic alterations in hepatocellular carcinoma cell lines analyzed by CGH and CGH array.

Hepatocellular carcinoma (HCC) is one of the most frequently occurring malignant tumors worldwide. The incidence of HCC is much higher in males than in females. In order to clarify the molecular basis of the male predominance in HCC, we have characterized the detailed genomic alterations in 5 hepatitis B virus integrated Korean HCC cell lines using G-banding, comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), PCR, and CGH array. The commonest alterations were observed in chromosome 7 and Y, as well as chromosomal regions 1q, 8q, 4q, and 16q. The most frequent aberration of genomic material was gain of 1q and loss of chromosome Y. Significant loss of DNA copy number of the cancer related genes that are located on chromosome Y was detected by CGH array. By investigating the karyotypes of the previously reported 21 male HCC cell lines, we found 18 HCC cell lines with Y chromosome loss, indicating that this loss is a significant feature of HCC cell lines. We propose that Y chromosome loss in HCC cell lines may be responsible for the preponderance of males in HCC and its significance may lead to further studies for better understanding of carcinogenesis in HCC.

Carcinoma, Hepatocellular↗
PubMed1999

Ploidy regulation of gene expression.

Microarray-based gene expression analysis identified genes showing ploidy-dependent expression in isogenic Saccharomyces cerevisiae strains that varied in ploidy from haploid to tetraploid. These genes were induced or repressed in proportion to the number of chromosome sets, regardless of the mating type. Ploidy-dependent repression of some G1 cyclins can explain the greater cell size associated with higher ploidies, and suggests ploidy-dependent modifications of cell cycle progression. Moreover, ploidy regulation of the FLO11 gene had direct consequences for yeast development.

Chitinases↗
PubMed2006

EWS-CREB1: a recurrent variant fusion in clear cell sarcoma--association with gastrointestinal location and absence of melanocytic differentiation.

PURPOSE: Clear cell sarcoma (CCS) usually arises in the lower extremities of young adults and is typically associated with a t(12;22) translocation resulting in the fusion of EWS (EWSR1) with ATF1, a gene encoding a member of the cyclic AMP-responsive element binding protein (CREB) family of transcription factors. CCS arising in the gastrointestinal tract is rare and its pathologic and molecular features are not well defined. EXPERIMENTAL DESIGN: We report a novel variant fusion of EWS to CREB1, a gene at 2q32 encoding another CREB family member highly related to ATF1, detected in three women with gastrointestinal CCS. All three cases contained an identical EWS-CREB1 fusion transcript that was shown by reverse transcription-PCR. In two of the cases tested, EWS gene rearrangement was also confirmed by fluorescence in situ hybridization and the EWS-CREB1 genomic junction fragments were isolated by long-range DNA PCR. RESULTS: Morphologically, all three tumors lacked melanin pigmentation. By immunohistochemistry, there was a strong and diffuse S100 protein reactivity, whereas all melanocytic markers were negative. Ultrastructurally, two of the cases lacked melanosomes. The melanocyte-specific transcript of MITF was absent in two cases, and only weakly expressed in the third case. The Affymetrix gene expression data available in one case showed lower expression of the melanocytic genes MITF, TYR, and TYRP1, compared with four EWS-ATF1-positive CCSs of non-gastrointestinal origin. CONCLUSIONS: EWS-CREB1 may define a novel subset of CCS that occurs preferentially in the gastrointestinal tract and shows little or no melanocytic differentiation. Thus, evidence of melanocytic lineage or differentiation is not a necessary feature of sarcomas with gene fusions involving CREB family members.

Activating Transcription Factor 1↗
PubMed2003

Genome-wide genetic characterization of bladder cancer: a comparison of high-density single-nucleotide polymorphism arrays and PCR-based microsatellite analysis.

Most human cancers are characterized by genomic instability, the accumulation of multiple genetic alterations, and allelic imbalance throughout the genome. Loss of heterozygosity (LOH) is a common form of allelic imbalance, and the detection of LOH has been used to identify genomic regions that harbor tumor suppressor genes and to characterize different tumor types, pathological stages and progression. Global patterns of LOH can be discerned by allelotyping of tumors with polymorphic genetic markers. Microsatellites are reliable genetic markers for studying LOH, but typically only a modest number of microsatellites are tested in LOH studies because the genotyping procedure can be laborious. Here we describe the use of a new alternative approach to comprehensive allelotyping in which samples are genotyped for nearly 1500 single-nucleotide polymorphism (SNP) loci distributed across all human autosomal arms. We examined the pattern of allelic imbalance in human transitional cell carcinomas of the urinary bladder including 36 primary tumors and 1 recurrent tumor with matched normal DNAs. The call rate for all SNPs was 78.5 +/- 1.87% overall samples. Overall, the median number of allelic imbalance was 47.5, ranging from 20 to 118. The mean number of allelic imbalances was 36.58, 51.30, and 67.78 for pT(a), pT(1), and > or =pT(2), respectively, and also increased by grade. The SNP microarray analysis result was validated by comparison with microsatellite allelotype analysis of 118 markers in the same tumors. Overall, the two methods produced consistent loss patterns at informative loci. The SNP assay discovered previously undiscovered allelic imbalances at chromosomal arms 12q, 16p, 1p, and 2q. The detection of LOH and other chromosomal changes using large numbers of SNP markers should enable rapid and accurate identification of allelic imbalance patterns that will facilitate the mapping and identification of important cancer genes. Moreover, SNP analysis raises the possibility of individual tumor genome-wide allelotyping with potential prognostic and diagnostic applications.

Carcinoma, Transitional Cell↗