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PubMed1982

Increased level of prolactin gene sequences in bromodeoxyuridine treated GH cells.

The 5-bromodeoxyuridine-resistant (BrdUrdr) derivative (F1BGH12C1) of prolactin nonproducing (PRL-) rat pituitary tumor cell-subclone GH12C1, synthesize prolactin (PRL) in the presence of the drug. Analysis of nuclear RNA isolated from BrdUrd treated F1BHG12C1 cells demonstrated several high molecular weight RNA PRL sequences, similar to those observed in the nuclear RNA fraction of PRL producing (PRL+) GH3 cells. No such RNAPRL sequences could be detected in nuclear RNA fraction of untreated F1 BGH12C1 cells. PRL sequences in the genome of GH3 (PRL+), GH12C1 (PRL-) and F1BGH12C1 (PRL-, BrdUrdr) GH cells could be identified by blot analysis in 4.8-5.2kb fragment of restriction endonuclease, Hind III digested DNA. Both PRL+ and PRL- cells seem to have approximately the same level of PRL gene sequences in total cell DNA. However Hind III digested DNA of BrdUrd treated F1BGH12C cells revealed the presence of significantly higher levels of PRL gene sequences, in comparison, to that observed in total DNA of untreated cells. The increased level of PRL gene sequences was dependent on the period of drug treatment and a parallel increase in the cytoplasmic RNAPRL sequences was also observed.

Animals↗
PubMed2003

Identification of expressed genes linked to malignancy of human colorectal carcinoma by parametric clustering of quantitative expression data.

BACKGROUND: Individual human carcinomas have distinct biological and clinical properties: gene-expression profiling is expected to unveil the underlying molecular features. Particular interest has been focused on potential diagnostic and therapeutic applications. Solid tumors, such as colorectal carcinoma, present additional obstacles for experimental and data analysis. RESULTS: We analyzed the expression levels of 1,536 genes in 100 colorectal cancer and 11 normal tissues using adaptor-tagged competitive PCR, a high-throughput reverse transcription-PCR technique. A parametric clustering method using the Gaussian mixture model and the Bayes inference revealed three groups of expressed genes. Two contained large numbers of genes. One of these groups correlated well with both the differences between tumor and normal tissues and the presence or absence of distant metastasis, whereas the other correlated only with the tumor/normal difference. The third group comprised a small number of genes. Approximately half showed an identical expression pattern, and cancer tissues were classified into two groups by their expression levels. The high-expression group had strong correlation with distant metastasis, and a poorer survival rate than the low-expression group, indicating possible clinical applications of these genes. In addition to c-yes, a homolog of a viral oncogene, prognostic indicators included genes specific to glial cells, which gives a new link between malignancy and ectopic gene expression. CONCLUSIONS: The malignancy of human colorectal carcinoma is correlated with a unique expression pattern of a specific group of genes, allowing the classification of tumor tissues into two clinically distinct groups.

Cluster Analysis↗
PubMed2004

Identification of necrosis-associated genes in glioblastoma by cDNA microarray analysis.

PURPOSE: In the field of cancer research, there has been a paucity of interest in necrosis, whereas studies focusing on apoptosis abound. In neuro-oncology, this is particularly surprising because of the importance of necrosis as a hallmark of glioblastoma (GBM), the most malignant and most common primary brain tumor, and the fact that the degree of necrosis has been shown to be inversely related to patient survival. It is therefore of considerable interest and importance to identify genes and gene products related to necrosis formation. EXPERIMENTAL DESIGN: We used a nylon cDNA microarray to analyze mRNA expression of 588 universal cellular genes in 15 surgically resected human GBM samples with varying degrees of necrosis. Gene expression was correlated with the degree of necrosis using rank correlation coefficients. The expression of identified genes was compared with their expression in tissue samples from 5 anaplastic astrocytomas (AAs). Immunostaining was used to determine whether genes showing the most positive correlation with necrosis were increasingly expressed in tumor tissues, as grade of necrosis increased. RESULTS: The hybridization results indicated that 26 genes showed significant correlation with the amount of necrosis. All 26 genes had functions associated with either Ras, Akt, tumor necrosis factor alpha, nuclear factor kappaB, apoptosis, procoagulation, or hypoxia. Nine genes were positively correlated with necrosis grade, and 17 genes were negatively correlated with necrosis grade. There were significant differences in the median expression levels of 3 of the 26 genes between grade III necrosis GBM and anaplastic astrocytoma (AA) samples; all but 1 of the genes had elevated expression when comparing necrosis grade III with AA samples. Two factors, the ephrin type A receptor 1 and the prostaglandin E(2) receptor EP4 subtype, not previously considered in this context, were highlighted because of their particularly high (positive) correlation coefficients; immunostaining showed the products of these two genes to be localized in perinecrotic and necrotic regions and to be overexpressed in grade III GBMs, but not AAs. These two molecules also showed significant correlation with survival of GBM patients (P = 0.0034) in a combined model. CONCLUSIONS: The application of cDNA expression microarray analysis has identified specific genes and patterns of gene expression that may help elucidate the molecular basis of necrogenesis in GBM. Additional studies will be required to further investigate and confirm these findings.

Brain Neoplasms↗
PubMed2006

Population-based retrieval of newborn dried blood spots for researching paediatric cancer susceptibility genes.

We have demonstrated the feasibility of linking newborn blood spots, population-based cancer incidence data and birth certificate data. Incident cases of acute lymphocytic leukaemia and population-based controls were ascertained. We retrieved dried blood spot specimens, isolated and amplified DNA, and assayed the cancer susceptibility genes GSTT1 and GSTM1. The double null genotype was over-represented in the cases, consistent with previous reports based on other epidemiological methods. The design avoids issues of participation bias by cases and controls and can be used to investigate interactions of susceptibility genes and xenobiotics in semi-ecological studies. It can be useful for generating or testing hypotheses on associations of other paediatric illness and environmental contaminants.

Case-Control Studies↗
PubMed2006

Novel genomic aberrations in testicular germ cell tumors by array-CGH, and associated gene expression changes.

INTRODUCTION: Testicular germ cell tumors of adolescent and young adult men (TGCTs) generally have near triploid and complex karyotypes. The actual genes driving the tumorigenesis remain essentially to be identified. MATERIALS AND METHODS: To determine the detailed DNA copy number changes, and investigate their impact on gene expression levels, we performed an integrated microarray profiling of TGCT genomes and transcriptomes. We analyzed 17 TGCTs, three precursor lesions, and the embryonal carcinoma cell lines, NTERA2 and 2102Ep, by comparative genomic hybridization microarrays (array-CGH), and integrated the data with transcriptome profiles of the same samples. RESULTS: The gain of chromosome arm 12p was, as expected, the most common aberration, and we found CCND2, CD9, GAPD, GDF3, NANOG, and TEAD4 to be the therein most highly over-expressed genes. Additional frequent genomic aberrations revealed some shorter chromosomal segments, which are novel to TGCT, as well as known aberrations for which we here refined boundaries. These include gains from 7p15.2 and 21q22.2, and losses of 4p16.3 and 22q13.3. Integration of DNA copy number information to gene expression profiles identified that BRCC3, FOS, MLLT11, NES, and RAC1 may act as novel oncogenes in TGCT. Similarly, DDX26, ERCC5, FZD4, NME4, OPTN, and RB1 were both lost and under-expressed genes, and are thus putative TGCT suppressor genes. CONCLUSION: This first genome-wide integrated array-CGH and gene expression profiling of TGCT provides novel insights into the genome biology underlying testicular tumorigenesis.

Adolescent↗
PubMed2001

Comprehensive genome sequence analysis of a breast cancer amplicon.

Gene amplification occurs in most solid tumors and is associated with poor prognosis. Amplification of 20q13.2 is common to several tumor types including breast cancer. The 1 Mb of sequence spanning the 20q13.2 breast cancer amplicon is one of the most exhaustively studied segments of the human genome. These studies have included amplicon mapping by comparative genomic hybridization (CGH), fluorescent in-situ hybridization (FISH), array-CGH, quantitative microsatellite analysis (QUMA), and functional genomic studies. Together these studies revealed a complex amplicon structure suggesting the presence of at least two driver genes in some tumors. One of these, ZNF217, is capable of immortalizing human mammary epithelial cells (HMEC) when overexpressed. In addition, we now report the sequencing of this region in human and mouse, and on quantitative expression studies in tumors. Amplicon localization now is straightforward and the availability of human and mouse genomic sequence facilitates their functional analysis. However, comprehensive annotation of megabase-scale regions requires integration of vast amounts of information. We present a system for integrative analysis and demonstrate its utility on 1.2 Mb of sequence spanning the 20q13.2 breast cancer amplicon and 865 kb of syntenic murine sequence. We integrate tumor genome copy number measurements with exhaustive genome landscape mapping, showing that amplicon boundaries are associated with maxima in repetitive element density and a region of evolutionary instability. This integration of comprehensive sequence annotation, quantitative expression analysis, and tumor amplicon boundaries provide evidence for an additional driver gene prefoldin 4 (PFDN4), coregulated genes, conserved noncoding regions, and associate repetitive elements with regions of genomic instability at this locus.

Animals↗
PubMed2006

Recognizing genes differentially regulated in vitro by the multiple endocrine neoplasia type 1 (MEN1) gene, using RNA interference and oligonucleotide microarrays.

BACKGROUND: Data on downstream effects of MEN1 gene inactivation is scarce. In an effort to identify genes regulated by MEN1, we designed a silencing experiment in a human endocrine pancreatic tumor cell line (BON1). METHODS: By using RNA interference, MEN1 mRNA expression was knocked-down by >85%. Gene expression was assessed by oligonucleotide microarrays and compared to expression in nonsilenced controls. We also investigated if genes were differentially expressed in 6 malignant endocrine pancreatic tumors (EPTs) with homozygous MEN1 inactivation compared to 2 without MEN1 gene alterations. RESULTS: Using a cut-off of > or =2 times, 66 genes were found to be upregulated, and 22 were downregulated in the MEN1-silenced clones. We corroborated the microarray findings by performing quantitative-PCR on the RNA from the silencing experiments for 7 of the 88 differentially regulated genes. Genes involved in endocrine cell fate determination, as well as genes known to be involved in NFkappaB, Notch, and Wnt signaling pathways, were among genes verified as differentially regulated in vitro. CONCLUSIONS: The demonstration of pathways affected by silencing of MEN1 in vitro provides novel insight into neoplastic processes of potential importance in vivo, which warrants further study.

Cell Line, Tumor↗
PubMed2006

Identification of differently expressed genes in human colorectal adenocarcinoma.

AIM: To investigate the differently expressed genes in human colorectal adenocarcinoma. METHODS: The integrated approach for gene expression profiling that couples suppression subtractive hybridization, high-throughput cDNA array, sequencing, bioinformatics analysis, and reverse transcriptase real-time quantitative polymerase chain reaction (PCR) was carried out. A set of cDNA clones including 1260 SSH inserts amplified by PCR was arrayed using robotic printing. The cDNA arrays were hybridized with fluorescent-labeled probes prepared from RNA of human colorectal adenocarcinoma (HCRAC) and normal colorectal tissues. RESULTS: A total of 86 genes were identified, 16 unknown genes and 70 known genes. The transcription factor Somult9 influencing cell differentiation was downregulated. At the same time, Heat shock protein 10 KDis downregulated and Calmoulin is up-regulated. CONCLUSION: Downregulation of heat shock protein 10 KD lost its inhibition of Ras, and then attenuated the Ras GTPase signaling pathway, increased cell proliferation and inhibited cell apoptosis. Down-regulated transcription factor Somult9 influences cell differentiation and cell-specific gene expression. Down-regulated Somult9 also decreases its binding to calmodulin, accumulates calmodulin as receptor-activated kinase and phosphorylase kinase due to the activation of PhK.

Adenocarcinoma↗
PubMed2004

Novel RNAs identified from an in-depth analysis of the transcriptome of human chromosomes 21 and 22.

In this report, we have achieved a richer view of the transcriptome for Chromosomes 21 and 22 by using high-density oligonucleotide arrays on cytosolic poly(A)(+) RNA. Conservatively, only 31.4% of the observed transcribed nucleotides correspond to well-annotated genes, whereas an additional 4.8% and 14.7% correspond to mRNAs and ESTs, respectively. Approximately 85% of the known exons were detected, and up to 21% of known genes have only a single isoform based on exon-skipping alternative expression. Overall, the expression of the well-characterized exons falls predominately into two categories, uniquely or ubiquitously expressed with an identifiable proportion of antisense transcripts. The remaining observed transcription (49.0%) was outside of any known annotation. These novel transcripts appear to be more cell-line-specific and have lower and less variation in expression than the well-characterized genes. Novel transcripts were further characterized based on their distance to annotations, transcript size, coding capacity, and identification as antisense to intronic sequences. By RT-PCR, 126 novel transcripts were independently verified, resulting in a 65% verification rate. These observations strongly support the argument for a re-evaluation of the total number of human genes and an alternative term for "gene" to encompass these growing, novel classes of RNA transcripts in the human genome.

Cell Line↗
PubMed1988

Oncogene induction of metastases.

A metastatic colony is the end result of a complex series of steps involving multiple gene products. In some cases, the augmented metastatic potential of certain tumour cells may be due to the increased expression of specific gene products which confer a selective advantage. Transfection of the c-Ha-ras oncogene into suitable recipient cells constitutes a powerful experimental model with which to identify putative gene products augmented in highly metastatic tumour cells compared to their non-metastatic counterparts. Transfection of the activated ras oncogene into 3T3 and 10T1/2 embryo fibroblasts, and adult rat fibroblasts, results in transformants which produce high numbers of spontaneous metastases in nude mice or syngeneic recipients. The ras oncogene will also increase the metastatic aggressiveness of murine tumours with low metastatic potential. However, the ras oncogene will not induce the metastatic phenotype in all recipient cells. Furthermore, specific genes such as adenovirus 2 E1A suppress the ability of ras to induce the metastatic phenotype. Natural 'suppressor' gene products may exist which render certain cells resistant to the induction of metastases by ras. Ras oncogene transfection induces the production of type IV collagenase, motility factors and growth factors. The ras oncogene therefore induces a cascade of gene functions leading to rapid progression to the metastatic phenotype. The mechanism of the induction probably involves complex interactions between the ras p21 product and multiple cellular gene products.

Animals↗
PubMed2005

Double minutes, cytogenetic equivalents of gene amplification, in human neoplasia - a review.

Double minutes are tiny spherical chromatin bodies of a few mega-base pairs of size which are found occasionally in hematopoietic neoplasia and more or less often in human solid tumors. They have been associated with worse prognosis and poor outcome of the malignancies where present. With the beginning era of molecular cytogenetics they could be defined as cytogenetic equivalents of amplified DNA sequences. The identification of involved chromosomal segments and their molecular nature led to the development of molecular genetic techniques for a rapid and reliable detection of prognostically important oncogene amplifications in human tumors and,as a consequence, to gene-targeted therapy.

Chromatin↗
PubMed2001

Resistance to cytotoxic agents.

Conflicting results have been published concerning the role of apoptosis impairment in cytotoxic drug resistance. This has shed important doubts on the currently accepted dogma, which presents apoptosis as a universal determinant of drug activity. These differing results are likely to be related to the cell-type specificity of apoptotic pathways. New genetic tools have recently been made available for the study of anticancer drug resistance. Differential or subtractive analyses of gene expression, especially using cDNA microarrays, allow the identification of multiple genes and complex pathways involved in drug activity, and the use of genetic suppressor elements represents a functional approach for the identification of resistance genes.

Antineoplastic Agents↗
PubMed1993

Clinicopathological features and prognostic significance of nucleoside diphosphate kinase/nm23 gene product in human pancreatic exocrine neoplasms.

Expression levels of nucleoside diphosphate (NDP) kinase/nm23 gene product in the surgically resected 59 human pancreatic exocrine neoplasms were examined immunohistochemically using antiNDP kinase antibody. Immunoreactivity for NDP kinase varied from one tumor to the other. Out of the 47 invasive pancreatic duct cell carcinomas examined, 31 (66%) tumors showed strong immunoreactivity for NDP kinase, whereas ten (83%) of 12 benign or less invasive tumors (in situ adenocarcinoma and mucin-producing tumor) showed negative or weak immunoreactivity (p < 0.01; Chi-square test). Overall survival of invasive pancreatic duct cell carcinomas with strong immunoreactivity for NDP kinase was poorer than those with negative or weak immunoreactivity (p < 0.03; generalized Wilcoxon test). Strong immunoreactivity for NDP kinase was associated with the type of histological differentiation, the presence of lymph node metastases (p < 0.05, respectively; Chi-square test), and the number of argyrophilic nucleolar organizer regions (p < 0.01; Student's t-test). These results suggest that NDP kinase/nm23 gene product expression was positively associated with tumor aggressiveness and poor survival of patients in human pancreatic exocrine neoplasms. They also suggest that NDP kinase expression is related to cell proliferation activity represented by the number of argyrophilic nucleolar organizer regions. Therefore, examining the level of NDP kinase/nm23 gene product could serve as a marker for malignant potentiality of pancreatic exocrine neoplasms.

Adult↗
PubMed1994

[Construction of human glioma cDNA library].

Total RNA from a human glioma was extracted by acid guanidinium-thiocyanate-chloroform one step method, and poly(A+)RNA was separated by affinity chromatography on oligo (dT) cellulose. The cDNA was synthesized by using poly (A+) RNA as template, the length of cDNA being 0.2-5 kb. The glioma cDNA inserts could be cloned into lambda gt11 vector, the resulting recombinant DNA was packaged in vitro. The cDNA library of 1.12 x 10(5) pfu/ml was obtained, and the cloning efficiency was 4.8 x 10(3)/ng cDNA. This library might contribute an important basis to study of the structure and function of human glioma genes.

Brain Neoplasms↗