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PubMed2004

Coordination of replication and transcription along a Drosophila chromosome.

The mechanisms by which metazoan origins of DNA replication are defined, regulated, and influenced by chromosomal events remain poorly understood. To gain insights into these mechanisms, we developed a systematic approach using a Drosophila high-resolution genomic microarray to determine replication timing, identify replication origins, and map protein-binding sites along a chromosome arm. We identify a defined temporal pattern of replication that correlates with the density of active transcription. These data indicate that the influence of transcription status on replication timing is exerted over large domains (>100 kb) rather than at the level of individual genes. We identify 62 early activating replication origins across the chromosome by mapping sites of nucleotide incorporation during hydroxyurea arrest. Using genome-wide location analysis, we demonstrate that the origin recognition complex (ORC) is localized to specific chromosomal sites, many of which coincide with early activating origins. The molecular attributes of ORC-binding sites include increased AT-content and association with a subset of RNA Pol II-binding sites. Based on these findings, we suggest that the distribution of transcription along the chromosome acts locally to influence origin selection and globally to regulate origin activation.

Animals↗
PubMed2005

DDEF1 is located in an amplified region of chromosome 8q and is overexpressed in uveal melanoma.

PURPOSE: The molecular pathogenesis of uveal melanoma is poorly understood but is usually accompanied by amplification of chromosome 8q, suggesting the activation of one or more oncogenes. We recently identified a gene expression profile that distinguishes low-grade from high-grade melanomas. In this profile, a cluster of genes at chromosome 8q was overexpressed in high-grade tumors, providing an opportunity to search for potential oncogenes in this region. EXPERIMENTAL DESIGN: Gene expression microarray analysis was done on 25 primary uveal melanomas. Microarray comparative genomic hybridization (CGH), quantitative PCR, and immunohistochemistry were done on a subset of these tumors. Cell motility was measured using a wound-healing assay. RESULTS: In melanomas analyzed for microarray gene expression and CGH, gain of chromosome 8q correlated most strongly with expression of DDEF1, a gene located at 8q24. In contrast, the nearby MYC oncogene exhibited no significant change in expression. Confirming the microarray findings, DDEF1 mRNA levels and protein expression were significantly higher in high-grade melanomas. Furthermore, ectopic expression of DDEF1 in low-grade melanoma cells resulted in a significant increase in cell motility, a feature of high-grade metastasizing cells. CONCLUSIONS: These findings suggest that DDEF1 overexpression may be a pathogenetically relevant consequence of chromosome 8q amplification, which commonly occurs in high-grade uveal melanomas. We conclude that DDEF1 may act as an oncogene in this cancer, and it may be a useful diagnostic marker and therapeutic target.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Chromosome abnormalities in ovarian adenocarcinoma: II. Prognostic impact of nonrandom chromosome abnormalities in 244 cases.

In a large series of ovarian carcinomas from 244 patients, 134 cases had chromosome rearrangements. We showed before that the pattern of chromosome breakpoints involved 21 separate chromosome regions nonrandomly and, in 90% of cases with breaks, the breakpoints occurred within 13 commonly involved regions. Log-rank and proportional hazards regression analyses showed that the aggregate presence of a chromosome breakpoint in any of 21 nonrandomly involved regions and breaks in 9 distinct regions (1p1, 1q2, 1p3, 3p1, 6p2, 11p1, 11q1, 12q2, and 13p1) were associated with reduced patient survival. Breakpoints in other areas of the genome, including other nonrandomly involved regions, were not associated with decreased survival. Because many cases had breakpoints in more than one nonrandomly involved region, proportional hazards regression was also used to analyze for effects of each nonrandomly involved region, controlling for effects of other regions. With this approach, only breakpoints within 1p1 and 3p1 retained independent, deleterious effects on survival. Similarly, when nonrandomly involved regions were entered into a proportional hazards model containing clinical variables associated with altered patient survival (tumor grade, tumor stage, and residual disease > 1 cm after resection), only 1p1 (P = 0.007) and 3p1 (P = 0.04) were associated with independent, negative effects on survival. These studies demonstrate that chromosome breakpoints within specific, nonrandomly involved chromosome regions are associated with impaired survival in ovarian cancers. Regions 1p1 and 3p1 are identified as areas of particular significance and are appropriate targets for analytical techniques such as SAGE and microarray analysis.

Adenocarcinoma↗
PubMed2006

Microarray expression analysis of meiosis and microsporogenesis in hexaploid bread wheat.

BACKGROUND: Our understanding of the mechanisms that govern the cellular process of meiosis is limited in higher plants with polyploid genomes. Bread wheat is an allohexaploid that behaves as a diploid during meiosis. Chromosome pairing is restricted to homologous chromosomes despite the presence of homoeologues in the nucleus. The importance of wheat as a crop and the extensive use of wild wheat relatives in breeding programs has prompted many years of cytogenetic and genetic research to develop an understanding of the control of chromosome pairing and recombination. The rapid advance of biochemical and molecular information on meiosis in model organisms such as yeast provides new opportunities to investigate the molecular basis of chromosome pairing control in wheat. However, building the link between the model and wheat requires points of data contact. RESULTS: We report here a large-scale transcriptomics study using the Affymetrix wheat GeneChip(R) aimed at providing this link between wheat and model systems and at identifying early meiotic genes. Analysis of the microarray data identified 1,350 transcripts temporally-regulated during the early stages of meiosis. Expression profiles with annotated transcript functions including chromatin condensation, synaptonemal complex formation, recombination and fertility were identified. From the 1,350 transcripts, 30 displayed at least an eight-fold expression change between and including pre-meiosis and telophase II, with more than 50% of these having no similarities to known sequences in NCBI and TIGR databases. CONCLUSION: This resource is now available to support research into the molecular basis of pairing and recombination control in the complex polyploid, wheat.

Chromosome Pairing↗
PubMed2006

COPA--cancer outlier profile analysis.

UNLABELLED: Chromosomal translocations are common in cancer, and in some cases may be causal in the progression of the disease. Using microarrays, in which the expression of thousands of genes are simultaneously measured, could potentially allow one to detect recurrent translocations for a particular cancer type. Standard statistical tests, such as the t-test are not suited for detecting these translocations, but a simple test based on robust centering and scaling of the data to help detect outlier samples, followed by a search for pairs of samples with mutually exclusive outliers, may be used to find genes involved in recurrent translocations. We have implemented this method, termed Cancer Outlier Profile Analysis (COPA) in an R package (that we call the copa package), and show its applicability on a publicly available dataset. AVAILABILITY: http://www.bioconductor.org

Algorithms↗
PubMed2005

Microarray analysis of pediatric ependymoma identifies a cluster of 112 candidate genes including four transcripts at 22q12.1-q13.3.

Ependymomas are glial cell-derived tumors characterized by varying degrees of chromosomal abnormalities and variability in clinical behavior. Cytogenetic analysis of pediatric ependymoma has failed to identify consistent patterns of abnormalities, with the exception of monosomy of 22 or structural abnormalities of 22q. In this study, a total of 19 pediatric ependymoma samples were used in a series of expression profiling, quantitative real-time PCR (Q-PCR), and loss of heterozygosity experiments to identify candidate genes involved in the development of this type of pediatric malignancy. Of the 12,627 genes analyzed, a subset of 112 genes emerged as being abnormally expressed when compared to three normal brain controls. Genes with increased expression included the oncogene WNT5A; the p53 homologue p63; and several cell cycle, cell adhesion, and proliferation genes. Underexpressed genes comprised the NF2 interacting gene SCHIP-1 and the adenomatous polyposis coli (APC)-associated gene EB1 among others. We validated the abnormal expression of six of these genes by Q-PCR. The subset of differentially expressed genes also included four underexpressed transcripts mapping to 22q12.313.3. By Q-PCR we show that one of these genes, 7 CBX7(22q13.1), was deleted in 55% of cases. Other genes mapping to cytogenetic hot spots included two overexpressed and three underexpressed genes mapping to 1q31-41 and 6q21-q24.3, respectively. These genes represent candidate genes involved in ependymoma tumorigenesis. To the authors' knowledge, this is the first time microarray analysis and Q-PCR have been linked to identify heterozygous/homozygous deletions.

Brain Neoplasms↗
PubMed2006

MIRA-assisted microarray analysis, a new technology for the determination of DNA methylation patterns, identifies frequent methylation of homeodomain-containing genes in lung cancer cells.

We present a straightforward and comprehensive approach for DNA methylation analysis in mammalian genomes. The methylated-CpG island recovery assay (MIRA), which is based on the high affinity of the MBD2/MBD3L1 complex for methylated DNA, has been used to detect cell type-dependent differences in DNA methylation on a microarray platform. The procedure has been verified and applied to identify a series of novel candidate lung tumor suppressor genes and potential DNA methylation markers that contain methylated CpG islands. One gene of particular interest was DLEC1, located at a commonly deleted area on chromosome 3p22-p21.3, which was frequently methylated in primary lung cancers and melanomas. Among the identified methylated genes, homeodomain-containing genes were unusually frequent (11 of the top 50 hits) and were targeted on different chromosomes. These genes included LHX2, LHX4, PAX7, HOXB13, LBX1, SIX2, HOXD3, DLX1, HOXD1, ONECUT2, and PAX9. The data show that MIRA-assisted microarray analysis has a low false-positive rate and has the capacity to catalogue methylated CpG islands on a genome-wide basis. The results support the hypothesis that cancer-associated DNA methylation events do not occur randomly throughout the genome but at least some are targeted by specific mechanisms.

Chromosome Mapping↗
PubMed2006

Meiotic and epigenetic aberrations in Dnmt3L-deficient male germ cells.

The DNA methyltransferase-like protein Dnmt3L is necessary for the establishment of genomic imprints in oogenesis and for normal spermatogenesis (Bourc'his et al., 2001; Hata et al., 2002). Also, a paternally imprinted gene, H19, loses DNA methylation in Dnmt3L-/- spermatogonia (Bourc'his and Bestor, 2004; Kaneda et al., 2004). To determine the reason for the impaired spermatogenesis in the Dnmt3L-/- testes, we have carried out a series of histological and molecular studies. We show here that Dnmt3L-/- germ cells were arrested and died around the early meiotic stage. A microarray-based gene expression-profiling analysis revealed that various gonad-specific and/or sex-chromosome-linked genes were downregulated in the Dnmt3L-/- testes. In contrast, expression of retrovirus-like intracisternal A-particle (IAP) sequences was upregulated; consistent with this observation, a specific IAP copy showed complete loss of DNA methylation. These findings indicate that Dnmt3L regulates germ cell-specific gene expression and IAP suppression, which are critical for male germ cell proliferation and meiosis.

Animals↗
PubMed2005

Array comparative genomic hybridisation (aCGH) analysis of premenopausal breast cancers from a nuclear fallout area and matched cases from Western New York.

High-resolution array comparative genomic hybridisation (aCGH) analysis of DNA copy number aberrations (CNAs) was performed on breast carcinomas in premenopausal women from Western New York (WNY) and from Gomel, Belarus, an area exposed to fallout from the 1986 Chernobyl nuclear accident. Genomic DNA was isolated from 47 frozen tumour specimens from 42 patients and hybridised to arrays spotted with more than 3000 BAC clones. In all, 20 samples were from WNY and 27 were from Belarus. In total, 34 samples were primary tumours and 13 were lymph node metastases, including five matched pairs from Gomel. The average number of total CNAs per sample was 76 (range 35-134). We identified 152 CNAs (92 gains and 60 losses) occurring in more than 10% of the samples. The most common amplifications included gains at 8q13.2 (49%), at 1p21.1 (36%), and at 8q24.21 (36%). The most common deletions were at 1p36.22 (26%), at 17p13.2 (26%), and at 8p23.3 (23%). Belarussian tumours had more amplifications and fewer deletions than WNY breast cancers. HER2/neu negativity and younger age were also associated with a higher number of gains and fewer losses. In the five paired samples, we observed more discordant than concordant DNA changes. Unsupervised hierarchical cluster analysis revealed two distinct groups of tumours: one comprised predominantly of Belarussian carcinomas and the other largely consisting of WNY cases. In total, 50 CNAs occurred significantly more commonly in one cohort vs the other, and these included some candidate signature amplifications in the breast cancers in women exposed to significant radiation. In conclusion, our high-density aCGH study has revealed a large number of genetic aberrations in individual premenopausal breast cancer specimens, some of which had not been reported before. We identified a distinct CNA profile for carcinomas from a nuclear fallout area, suggesting a possible molecular fingerprint of radiation-associated breast cancer.

Adult↗
PubMed2004

Molecular karyotyping using an SNP array for genomewide genotyping.

BACKGROUND: Chromosomal imbalances are a major cause of developmental defects as well as cancer and often constitute the key in identification of novel disease related genes. Classical cytogenetic methods are limited in resolution and dependent on highly skilled labour, while methods with higher resolution, based on molecular cytogenetics approaches such as matrix CGH, are not widely available. METHODS: We have developed and evaluated a method we term "molecular karyotyping", using readily available and easy to handle oligonucleotide arrays originally designed for parallel genomewide analysis of over 10,000 SNPs. We show that we can easily and reliably detect unbalanced chromosomal aberrations of various sizes from as little as 250 ng of DNA on a single microarray, based on fluorescence intensity information from clusters of SNPs. RESULTS: We determined the resolution of this method through analysis of 20 trios with 21 previously confirmed subtle aberrations sizing between 0.2 and 13 Mb. Duplications and deletions of at least 5 Mb in size were reliably detectable, but detection of smaller aberrations was dependent on the number of SNPs they contained, thus seven of 10 different deletions analysed, with sizes ranging from 0.2 to 3.7 Mb, were not detectable due to insufficient SNP densitiy in the respective region. CONCLUSIONS: Deduction of reliable cut off levels for array peaks in our series of well characterised patients allows the use of the GeneChip Mapping 10K SNP array for performing rapid molecular karyotyping from small amounts of DNA for the detection of even subtle deletions and duplications with high sensitivity and specificity.

Chromosome Aberrations↗
PubMed2001

Functional genomics of oxidant-induced lung injury.

In summary, acute lung injury is a severe (>40% mortality) respiratory disease associated with numerous precipitating factors. Despite extensive research since its initial description over 30 years ago, questions remain about the basic pathophysiological mechanisms and their relationship to therapeutic strategies. Histopathology reveals surfactant disruption, epithelial perturbation and sepsis, either as initiating factors or as secondary complications, which in turn increase the expression of cytokines that sequester and activate inflammatory cells, most notably, neutrophils. Concomitant release of reactive oxygen and nitrogen species subsequently modulates endothelial function. Together these events orchestrate the principal clinical manifestations of the syndrome, pulmonary edema and atelectasis. To better understand the gene-environmental interactions controlling this complex process, we examined the relative sensitivity of inbred mouse strains to acute lung injury induced by ozone, ultrafine PTFE, or fine particulate NiSO4 (0.2 microm MMAD, 15-150 microg/m3). Measuring survival time, protein and neutrophils in bronchoalveolar lavage, lung wet: dry weight, and histology, we found that these responses varied between inbred mouse strains, and susceptibility is heritable. To assess the molecular progression of NiSO4-induced acute lung injury, temporal relationships of 8734 genes and expressed sequence tags were assessed by cDNA microarray analysis. Clustering of co-regulated genes (displaying similar temporal expression patterns) revealed the altered expression of relatively few genes. Enhanced expression occurred mainly in genes associated with oxidative stress, anti-proteolytic function, and repair of the extracellular matrix. Concomitantly, surfactant proteins and Clara cell secretory protein mRNA expression decreased. Genome wide analysis of 307 mice generated from the backcross of resistant B6xA F1 with susceptible A strain identified significant linkage to a region on chromosome 6 (proposed as Aliq4) and suggestive linkages on chromosomes 1, 8, and 12. Combining of these QTLs with two additional possible modifying loci (chromosome 9 and 16) accounted for the difference in survival time noted in the A and B6 parental strains. Combining these findings with those of the microarray analysis has enabled prioritization of candidate genes. These candidates, in turn, can be directed to the lung epithelium in transgenic mice or abated in inducible and constitutive gene-targeted mice. Initial results are encouraging and suggest that several of these mice vary in their susceptibility to oxidant-induced lung injury. Thus, these combined approaches have led to new insights into functional genomics of lung injury and diseases.

Animals↗
PubMed2004

Genetic analysis of fibrosarcoma of bone, a rare tumour entity closely related to osteosarcoma and malignant fibrous histiocytoma of bone.

Fibrosarcoma (FS) of bone is an extremely rare and genetically uncharacterised malignant tumour arising in the skeleton. On the basis of clinicopathologic features it appears to be closely related to either fibroblastic osteosarcoma (OS) or malignant fibrous histiocytoma (MFH) of bone. In this study, 27 decalcified, paraffin-embedded FS of bone were collected for genetic and immunohistochemical characterisation. Good quality DNA, suitable for genetic analyses, was isolated from nine cases (7 primary tumours, 1 local recurrence, and 1 lung metastasis), which were analysed by comparative genomic hybridisation (CGH) on chromosomes and DNA microarrays. DNA sequence copy number changes were found in five out of seven primary tumours (72%), as well as in both, the local recurrence and the metastatic lesion, by CGH on chromosomes. The most frequent aberration was gain of the chromosomal region 22q, which was present in four out of the five primary tumours with genetic changes, in the local recurrence and, as the sole genetic aberration, in the lung metastasis. DNA microarray analysis showed that gain of the platelet-derived growth factor beta (PDGF-B) gene (located at 22q12.3-q13.1) was the most frequent gene imbalance, which was present in three out of the five analysed tumours. In these three cases, real-time PCR revealed a 2.1- to 2.7-fold increase of PDGF-B gene copy numbers. By immunohistochemistry, a positive reaction for B-chain-containing PDGF proteins was revealed in all the cases showing gain of 22q. A more extensive immunohistochemical analysis identified the presence of PDGF-B proteins in 8/20 primary FS of bone (40%), 3/3 lung metastases and in 1/2 local recurrences. A simultaneous positive reaction for PDGF-B proteins and PDGF receptors was found in two third of PDGF-B-positive cases (8/12). Taken together, the genetic and immunohistochemical data indicate that over-representation of the chromosomal region 22q, including particularly the PDGF-B gene, may be important for the pathogenesis of FS of bone. Our results also demonstrate that CGH on chromosomes and DNA microarrays are suitable for the genetic characterisation of decalcified, paraffin-embedded tumour tissue samples and may facilitate, combined with other techniques, the rapid acquisition of data providing insight into the molecular genetic and biologic basis of rare bone sarcomas. Moreover, these findings suggest the possible presence of an autocrine loop in FS of bone, which might be taken into account for planning innovative therapeutic strategies for patients unresponsive to conventional treatments.

Adult↗
PubMed2001

Genetic analysis of early- versus late-stage ovarian tumors.

In the United States, ovarian cancer is the fourth most common cause of cancer-related deaths among women. The most important prognostic factor for this cancer is tumor stage, or extent of disease at diagnosis. Although women with low-stage tumors have a relatively good prognosis, most women diagnosed with late-stage disease eventually succumb to their cancer. In an attempt to understand early events in ovarian carcinogenesis, and to explore steps in its progression, we have applied multiple molecular genetic techniques to the analysis of 21 early-stage (stage I/II) and 17 advanced-stage (stage III/IV) ovarian tumors. These techniques included expression profiling with cDNA microarrays containing approximately 18,000 expressed sequences, and comparative genomic hybridization to address the chromosomal locations of copy number gains as well as losses. Results from the analysis indicate that early-stage ovarian cancers exhibit profound alterations in gene expression, many of which are similar to those identified in late-stage tumors. However, differences observed at the genomic level suggest differences between the early- and late-stage tumors and provide support for a progression model for ovarian cancer development.

Disease Progression↗
PubMed2005

Microarray-based comparative genomic hybridization of pheochromocytoma cell lines from neurofibromatosis knockout mice reveals genetic alterations similar to those in human pheochromocytomas.

Somatic genetic aberrations have been identified in both sporadic pheochromocytomas and those associated with familial tumor syndromes; however, individual variations between human tumors and the absence of in vitro human pheochromocytoma models hinder efforts to understand the roles of those aberrations in tumorigenesis. Pheochromocytomas occur frequently in neurofibromatosis knockout mice and we have recently developed cell lines from those tumors. The availability of multiple tumors from genetically identical animals provides a powerful tool for understanding the pathobiology of pheochromocytomas. For the present investigation, we performed a genomic scanning analysis of four mouse pheochromocytoma cell lines by standard cytogenetics and microarray-based comparative genomic hybridization in order to identify genetic common denominators. All of the lines showed losses of most or all of chromosome 9; three lines lost most or all of chromosome 4. Mouse chromosome 4 is homologous to human chromosome 1p, which is the most frequent deletion in human pheochromocytomas. Mouse chromosome 9 shows large areas of homology to human 3p, 3q, and 11q, which are also frequently deleted. These comparisons suggest that genetic mechanisms in the genesis of pheochromocytomas may be similar across species. Additional changes that may be specific to this model included complete or partial gains of chromosome 12 as seen in 3 of the 4 lines analyzed by array CGH.

Adrenal Gland Neoplasms↗
PubMed2006

Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both relentlessly progressive and ultimately fatal neurological disorders. ALS is familial in approximately 10% of cases and FTD in approximately 30%. Inheritance is usually autosomal dominant with variable penetrance. Phenotypic overlap between ALS and FTD can occur within the same kindred. Mutations in copper/zinc superoxide dismutase 1 (SOD1) are found in approximately 20% of familial and approximately 3% of sporadic ALS cases but are not associated with dementia. Mutations in microtubule associated protein tau (MAPT) are detected in approximately 30% of familial FTD kindreds. Dominant ALS with FTD has previously been linked to 9q21 and pure ALS to loci on 16q21, 18q21, 20p13. Here we report the results of a genome-wide linkage study in a large ALS and FTD kindred using Affymetrix 10K GeneChip microarrays. Linkage analysis of single nucleotide polymorphism (SNP) data identified consistently positive log of the odds (LOD) scores across chromosome 9p (maximal LOD score of 2.4). Fine mapping the region with microsatellite markers generated a maximal multipoint LOD score of 3.02 (theta = 0) at D9S1878. Recombination narrowed the conserved haplotype to 12 cM (11 Mb) at 9p13.2-21.3 (flanking markers D9S2154 and D9S1874). Bioinformatic analysis of the region has identified 103 known genes.

Adult↗
PubMed2006

Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas.

Integrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Notably, the pattern of genetic and epigenetic inactivation differed among B-NHL subtypes. Thus, the P53-inducible PIG7/LITAF was silenced by homozygous deletion in primary mediastinal B-cell lymphoma and by promoter hypermethylation in germinal center lymphoma, the proapoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the proapoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma, and INK4c/P18 was silenced by biallelic mutation in mantle-cell lymphoma. Our microarray strategy has identified novel candidate tumor suppressor genes inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Molecular analysis of anoikis resistance in oral cavity squamous cell carcinoma.

Oral cavity squamous cell carcinoma (OSCC) is one of the leading causes of cancer deaths worldwide and most of these deaths result from local-regional recurrence and metastases. Evasion of apoptosis is an important hallmark of cancer development and progression, and previous studies have shown that evasion of anoikis, or detachment-induced apoptosis, correlates with a more aggressive phenotype of carcinoma cells in OSCC. To elucidate the cytogenetic and molecular characteristics of anoikis resistance, we generated several cell lines and clones that displayed this cellular phenotype. To test the hypothesis that chromosomal alterations may underlie this phenotypic transformation, we used karyotype analysis to observe changes in the chromosomal structure of anoikis-sensitive and anoikis-resistant cell lines. We further hypothesized that a unique pattern of gene expression was induced by cell-detachment of anoikis-resistant cell lines, and cDNA microarray analysis was performed using a panel of anoikis-resistant oral cancer cell lines grown under attached and detached growth conditions. We identified S100P, KLK6 and CTNNAL1 as genes whose expression levels were differentially regulated in the anoikis-resistant cell lines compared to the anoikis-sensitive cells under detached conditions. These results were verified using real-time RT-PCR. The anoikis-resistant phenotype of squamous cell carcinoma has a distinct genetic expression pattern that is marked by chromosomal alterations that may contribute to differential expression of genes involved in diverse cellular functions. Therapies targeting these potential mediators of anoikis resistance may prove to be beneficial in the treatment of metastatic squamous cell carcinoma.

Animals↗
PubMed2005

Cryptic duplication and deletion of 9q34.3 --> qter in a family with a t(9;22)(q34.3;p11.2).

A newborn male was referred for genetic evaluation because of multiple congenital abnormalities. Physical findings included a round face, telecanthus, hypertelorism, a short upturned nose with anteverted nares, small ears, micrognathia, short toes, and congenital heart disease. Chromosome analysis detected a possible deletion of 9qter because of satellite material on 9qter. Delineation by FISH and microarray CGH studies showed 46,XY,der(9)t(9;22)(q34.3;p11.2). The mother and maternal grandfather had a balanced t(9;22)(q34.3;p11.2) rearrangement. Also, the maternal great-aunt of the propositus was found to have a duplication of 9q34.3 --> qter. FISH was required to delineate her karyotype, which was 46,XX.ish der(22)t(9;22)(q34.3;p11.2). This maternal great-aunt and one of her daughters (cytogenetics not done) have a relatively normal phenotype, only reporting mild learning disabilities in school. Since the 22p material involved in this rearrangement is clinically irrelevant, this report describes an individual with a pure deletion of 9q34.3 --> qter and another with a pure duplication of 9q34.3 --> qter.

Child↗