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Genomic Alterations (genomic + alteration)
Selected AbstractsErratum: Genomic alterations in histopathologically normal breast tissue from BRCA1 mutation carriers may be caused by BRCA1 haploinsufficiencyGENES, CHROMOSOMES AND CANCER, Issue 8 2010Karin Rennstam No abstract is available for this article. [source] Determination of genomic damage in neuroblastic tumors by arbitrarily primed PCR: MYCN amplification as a marker for genomic instability in neuroblastomasNEUROPATHOLOGY, Issue 3 2006Jorge Muñoz The aim of this study is to establish an estimation of the global genomic alteration in neuroblastic tumors (ganglioneuromas, ganglioneuroblastomas and neuroblastomas) and correlate them with different clinical parameters (age, sex, diagnosis, Shimada index, proliferation index, tumor location, and 1p and v-myc avian myelocitomatosis viral-related (MYCN) status) in order to find new molecular and/or prognostic markers for neuroblastoma. To assess the genomic damage in neuroblastic tumors, we used an arbitrarily primed PCR approach, a technique based on the reproducibility of band profiles obtained by a PCR with a low annealing temperature in its first cycles. Genomic damage was assessed by comparing band profiles of tumors and normal paired samples. Gains and losses in the intensity of the bands were computerized and referred to the total number of bands analyzed. We found a higher genomic damage fraction (GDF) in the female's group (U-Mann,Whitney, P = 0.025), but we could not find any association between GDF and tumor location, proliferation index, diagnosis or age of the patient. There was no relationship between 1p status and GDF, but tumors with MYCN amplification had a slightly higher GDF. MYCN amplification might in some way contribute to genomic instability of neuroblastomas. [source] Transcriptional profiling of brain-derived-neurotrophic factor-induced neuronal plasticity: A novel role for nociceptin in hippocampal neurite outgrowthDEVELOPMENTAL NEUROBIOLOGY, Issue 4 2006Robert H. Ring Abstract Brain derived neurotrophic factor (BDNF) exhibits a sequence of actions on neurons ranging from acute enhancement of transmission to long-term promotion of neurite outgrowth and synaptogenesis associated with learning and memory. The manifold effects of BDNF on neuronal modifications may be mediated by genomic alterations. We previously found that BDNF treatment acutely increases transcription of the synaptic vesicle protein Rab3A, required for trophin-induced synaptic plasticity, as well as the peptide VGF, which increases during learning. To elucidate comprehensive transcriptional programs associated with short- and long-term BDNF exposure, we now examine mRNA abundance and complexity using Affymetrix GeneChips in cultured hippocampal neurons. Consistent with the modulation of synaptic plasticity, BDNF treatment (3,6 h) induced mRNAs encoding the synapse-associated proteins synaptojanin 2, neuronal pentraxin 1, septin 9, and ryanodine receptor 2. BDNF also induced expression of mRNAs encoding neuropeptides (6,12 h), including prepronociceptin, neuropeptide Y, and secretogranin. To determine whether these neuropeptides induced by BDNF mediate neuronal development, we examined their effects on hippocampal neurons. The four mature peptides derived from post-translational processing of the ppNociceptin propeptide induced the expression of several immediate early genes in hippocampal cultures, indicating neuronal activation. To examine the significance of activation, the effects of nociceptin (orphanin FQ) and nocistatin on neurite outgrowth were examined. Quantitative morphometric analysis revealed that nociceptin significantly increased both average neurite length and average number of neurites per neuron, while nocistatin had no effect on these parameters. These results reveal a novel role for nociceptin and suggest that these neuropeptide systems may contribute to the regulation of neuronal function by BDNF. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Induction of V(D)J-mediated recombination of an extrachromosomal substrate following exposure to DNA-damaging agentsENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 6 2007Robert L. Pinsonneault Abstract V(D)J recombinase normally mediates recombination signal sequence (RSS) directed rearrangements of variable (V), diversity (D), and joining (J) germline gene segments that lead to the generation of diversified T cell receptor or immunoglobulin proteins in lymphoid cells. Of significant clinical importance is that V(D)J-recombinase-mediated rearrangements at immune RSS and nonimmune cryptic RSS (cRSS) have been implicated in the genomic alterations observed in lymphoid malignancies. There is growing evidence that exposure to DNA-damaging agents can increase the frequency of V(D)J-recombinase-mediated rearrangements in vivo in humans. In this study, we investigated the frequency of V(D)J-recombinase-mediated rearrangements of an extrachromosomal V(D)J plasmid substrate following exposure to alkylating agents and ionizing radiation. We observed significant dose- and time-dependent increases in V(D)J recombination frequency (V(D)J RF) following exposure to ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) but not a nonreactive analogue, methylsulfone (MeSulf). We also observed a dose-dependent increase in V(D)J RF when cells were exposed to gamma radiation. The induction of V(D)J rearrangements following exposure to DNA-damaging agents was not associated with an increase in the expression of RAG 1/2 mRNA compared to unexposed controls or an increase in expression of the DNA repair Ku70, Ku80 or Artemis proteins of the nonhomologous end joining pathway. These studies demonstrate that genotoxic alkylating agents and ionizing radiation can induce V(D)J rearrangements through a cellular response that appears to be independent of differential expression of proteins involved with V(D)J recombination. Environ. Mol. Mutagen., 2007. © 2007 Wiley-Liss, Inc. [source] Multiple genomic alterations on 21q22 predict various TMPRSS2/ERG fusion transcripts in human prostate cancersGENES, CHROMOSOMES AND CANCER, Issue 11 2007Wennuan Liu A number of TMPRSS2/ERG fusion transcripts have been reported since the discovery that recurrent genomic rearrangements result in the fusion of TMPRSS2 and ETS family member genes. In this article we present evidence demonstrating that multiple genomic alterations contribute to the formation of various TMPRSS2/ERG transcripts. Using allele-specific analysis of the data generated from the GeneChip 500K SNP array we observed both hemizygous and homozygous deletions occurring at different locations between and within TMPRSS2 and ERG in prostate cancers. The 500K SNP array enabled us to fine map the start and end of each deletion to specific introns of these two genes, and to predict a variety of fusion transcripts, including a new form which was confirmed by sequence analysis of the fusion transcripts in various tumors. We also inferred that translocation is an additional mechanism of fusion for these two genes in some tumors, based on largely diploid genomic DNA between TMPRSS and ERG, and different fusion transcripts produced in these tumors. Using a bioinformatics approach, we then uncovered the consensus sequences in the regions harboring the breakpoints of the deletions. These consensus sequences were homologous to the human Alu-Sq and Alu-Sp subfamily consensus sequences, with more than 80% homology. The presence/absence of Alu family consensus sequence in the introns of TMPRSS2 and ERG correlates with the presence/absence of fusion transcripts of theses two genes, indicating that these consensus sequences may contribute to genomic deletions and the fusion of TMPRSS2 and ERG in prostate cancer. © 2007 Wiley-Liss, Inc. [source] Quantitative microsatellite analysis to delineate the commonly deleted region 1p22.3 in mantle cell lymphomasGENES, CHROMOSOMES AND CANCER, Issue 10 2006Asha Balakrishnan The molecular pathogenesis of mantle cell lymphomas (MCL), a subset of B-cell non-Hodgkin's lymphomas with a poor prognosis, is still poorly understood. In addition to the characteristic primary genetic alteration t(11;14)(q13;q32), several further genetic changes are present in most cases. One of the most frequent genomic imbalances is the deletion of 1p22.1,p31.1 observed in nearly one-third of MCL cases. This might indicate the presence of tumor suppressor gene(s) in this critical region of deletion. Quantitative microsatellite analysis (QuMA) is a real-time PCR-based method to detect DNA copy number changes. Since QuMA has the resolving power to detect subtle genomic alterations, including homozygous deletions, this may help to identify candidate tumor suppressor genes from deleted regions. To gain more insight into the molecular pathogenesis of MCL, QuMA was performed on genomic DNA from 57 MCL cases. Eight microsatellite loci mapping to the chromosomal region 1p22.3 were analyzed. Losses were observed in 51 of the 57 (,89.5%) samples. Two cases showed a homozygous deletion at the locus containing the gene SH3GLB1, which plays a key role in Bax-mediated apoptosis. Two hotspots with copy number losses were detected at chromosomal localizations 85.4 and 86.6 Mb encompassing BCL10 and CLCA2. Both the genes seem to be attractive candidates to study tumor suppressor function in MCL. This article contains Supplementary material available at http://www.interscience.wiley.com/jpages/1045,2257/suppmat. © 2006 Wiley-Liss, Inc. [source] Aberrant expression of cell-cycle regulator cyclin D1 in breast cancer is related to chromosomal genomic instabilityGENES, CHROMOSOMES AND CANCER, Issue 3 2002Jia-Chyi Lung To account for the accumulation of genomic alterations required for tumor progression, it has been suggested that the genomes of cancer cells are unstable and that this instability results from defective mutators (the "mutator phenotype" theory). To examine the hypothesis that abnormal cell-cycle regulators act as the mutators contributing to genomic instability, the present study, based on primary tumor tissues from 71 patients with breast cancer, was performed to determine whether there was an association between aberrant expression of cell-cycle regulators (cyclin A, cyclin D1, cyclin E, RB1, p21, and p27) and chromosomal instability. Comparative genomic hybridization was used to measure chromosomal changes, reflecting genomic instability in individual tumors, whereas immunohistochemistry was used to detect aberrant expression of cell-cycle regulators. Overexpression of cyclin D1 was found to be significantly correlated with increased chromosomal instability (defined as harboring more than 7 chromosomal changes), with 63% of tumors overexpressing and 27% of tumors not overexpressing, with cyclin D1 showing chromosomal instability (P < 0.05). Interestingly, this relationship was independent of cell outgrowth (as detected by the proliferation marker Ki-67) and was particularly significant in tumors not expressing p27 or in tumors with detectable RB1. These results suggest that cyclin D1 plays an alternative role in the regulation of genomic stability. © 2002 Wiley-Liss, Inc. [source] Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer,HUMAN MUTATION, Issue 12 2007Susan J. Ramus Abstract A total of 283 epithelial ovarian cancer families from the United Kingdom (UK) and the United States (US) were screened for coding sequence changes and large genomic alterations (rearrangements and deletions) in the BRCA1 and BRCA2 genes. Deleterious BRCA1 mutations were identified in 104 families (37%) and BRCA2 mutations in 25 families (9%). Of the 104 BRCA1 mutations, 12 were large genomic alterations; thus this type of change represented 12% of all BRCA1 mutations. Six families carried a previously described exon 13 duplication, known to be a UK founder mutation. The remaining six BRCA1 genomic alterations were previously unreported and comprised five deletions and an amplification of exon 15. One of the 25 BRCA2 mutations identified was a large genomic deletion of exons 19,20. The prevalence of BRCA1/2 mutations correlated with the extent of ovarian and breast cancer in families. Of 37 families containing more than two ovarian cancer cases and at least one breast cancer case with diagnosis at less than 60 years of age, 30 (81%) had a BRCA1/2 mutation. The mutation prevalence was appreciably less in families without breast cancer; mutations were found in only 38 out of 141 families (27%) containing two ovarian cancer cases only, and in 37 out of 59 families (63%) containing three or more ovarian cancer cases. These data indicate that BRCA1 and BRCA2 are the major susceptibility genes for ovarian cancer but that other susceptibility genes may exist. Finally, it is likely that these data will be of clinical importance for individuals in families with a history of epithelial ovarian cancer, in providing accurate estimates of their disease risks. Hum Mutat 28(12), 1207,1215, 2007. © 2007 Wiley-Liss, Inc. [source] Approaches to identify genes for complex human diseases: Lessons from Mendelian disorders,,HUMAN MUTATION, Issue 4 2003Michael Dean Abstract The focus of most molecular genetics research is the identification of genes involved in human disease. In the 20th century, genetics progressed from the rediscovery of Mendel's Laws to the identification of nearly every Mendelian genetic disease. At this pace, the genetic component of all complex human diseases could be identified by the end of the 21st century, and rational therapies could be developed. However, it is clear that no one approach will identify the genes for all diseases with a genetic component, because multiple mechanisms are involved in altering human phenotypes, including common alleles with small to moderate effects, rare alleles with moderate to large effects, complex gene,gene and gene,environment interactions, genomic alterations, and noninherited genetic effects. The knowledge gained from the study of Mendelian diseases may be applied to future research that combines linkage-based, association-based, and sequence-based approaches to detect most disease alleles. The technology to complete these studies is at hand and requires that modest improvements be applied on a wide scale. Improved analytical tools, phenotypic characterizations, and functional analyses will enable complete understanding of the genetic basis of complex diseases. Hum Mutat 22:261,274, 2003. Published © 2003 Wiley-Liss, Inc. [source] Assessment of genomic instability in breast cancer and uveal melanoma by random amplified polymorphic DNA analysisINTERNATIONAL JOURNAL OF CANCER, Issue 2 2002Sarantos Papadopoulos Abstract Some types of cancer have been associated with abnormal DNA fingerprinting. We used random amplified polymorphic DNA (RAPD) to generate fingerprints that detect genomic alterations in human breast cancer. Primers were designed by choosing sequences involved in the development of DNA mutations. Seventeen primers in 44 different combinations were used to screen a total of 6 breast cancer DNA/normal DNA pairs and 6 uveal melanoma DNA/normal DNA pairs. Forty-five percent of these combinations reliably detected quantitative differences in the breast cancer pairs, while only 18% of these combinations detected differences in the uveal melanoma pairs. Fourteen (32%) and 12 (27%) primers generated a smear or did not produce any band patterns in the first and second cases, respectively. Taking into account the ability of RAPD to screen the whole genome, our results suggest that the genomic damage in breast cancer is significantly higher than in uveal melanoma. Our study confirms other reports that the molecular karyotypes produced with random priming, called amplotypes, are very useful for assessing genomic damage in cancer. © 2002 Wiley-Liss, Inc. [source] Establishment of OC3 oral carcinoma cell line and identification of NF-,B activation responses to areca nut extractJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 2 2004Shu-Chun Lin Background:, Cell lines derived from oral squamous cell carcinoma (OSCC) exposed to variable etiological factors can bestow advantages in understanding the molecular and cellular alterations pertaining to environmental impacts. Most OSCC cell lines have been established from smoker patients or areca chewing/smoker patients, carrying the genomic alterations in p53. Methods:, A new cell line, oral carcinoma 3 (OC3), was established from an OSCC in a long-term areca (betel) chewer who does not smoke. Cellular and molecular features of OC3 were determined by variable assays. Results:, The cultured monolayer cells were mainly polygonal and had the expression of cytokeratin 14. The chromosomal analysis using comparative genomic hybridization has revealed the gain in chromosomes 1q, 5q, and 8q, the loss in 4q, 6p, and 8p as well as the gain of entire chromosome 20. Loss of heterozygosity and instability in multiple microsatellite markers in chromosome 4q were also noted. OC3 cells bear wild-type p53 coding sequence and have a high level of p53 expression. Its p21 expression was similar to that in normal human oral keratinocyte (NHOK). Interestingly, activation of nuclear factor ,B (NF-,B) in OC3 cells following the treatment of areca nut extract was observed. Conclusion:, OC3 cell line could be valuable in understanding the genetic impairments and phenotypic changes associated with areca in oral keratinocyte. [source] Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer,THE JOURNAL OF PATHOLOGY, Issue 4 2008Y Tsukamoto Abstract Genomic copy number aberrations (CNAs) are believed to play a major role in the development and progression of human cancers. Although many CNAs have been reported in gastric cancer, their genome-wide transcriptional consequences are poorly understood. In this study, to reveal the impact of CNAs on genome-wide expression in gastric cancer, we analysed 30 cases of gastric cancers for their CNAs by array comparative genomic hybridization (array CGH) and 24 of these 30 cases for their expression profiles by oligonucleotide-expression microarray. We found that with the application of laser microdissection, most CNAs were detected at higher frequency than in previous studies. Notably, gain at 20q13 was detected in almost all cases (97%), suggesting that this may play an important role in the pathogenesis of gastric cancer. By comparing the array CGH data with expression profiles of the same samples, we showed that both genomic amplification and deletion strongly influence the expression of genes in altered genomic regions. Furthermore, we identified 125 candidate genes, consisting of 114 up-regulated genes located in recurrent regions (>10%) of amplification and 11 down-regulated genes located in recurrent regions of deletion. Up-regulation of several candidate genes, such as CDC6, SEC61G, ANP32E, BYSL and FDFT1, was confirmed by immunohistochemistry. Interestingly, some candidate genes were localized at genomic loci adjacent to well-known genes such as EGFR, ERBB2 and SMAD4, and concordantly deregulated by genomic alterations. Based on these results, we propose that our list of candidate genes may contain novel genes involved in the pathogenesis of advanced gastric cancer. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Putting the colours into chromogenic in situ hybridization (CISH)THE JOURNAL OF PATHOLOGY, Issue 1 2006J Shipley Abstract Recurrent genomic alterations are the hallmarks of particular cancers. Application of molecular cytogenetic technologies to tumour material in order to detect these alterations has become important for molecular diagnostics and research. A dual-colour chromogenic in situ hybridization (dc-CISH) method described recently in the Journal of Pathology has the advantage of visualizing two probes simultaneously with the ability to discern morphological features. In addition, the bright field microscopy required is readily accessible to many laboratories. The approach has been validated by comparison of results with standard analyses for HER-2 amplification status in formalin-fixed, paraffin-embedded breast cancers and is applicable to the analysis of other clinically relevant genomic aberrations as well as of use in research investigations. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Integrated genomic and expression profiling in mantle cell lymphoma: identification of gene-dosage regulated candidate genesBRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2008Margit Schraders Summary Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation and several other cytogenetic aberrations, including heterozygous loss of chromosomal arms 1p, 6q, 11q and 13q and/or gains of 3q and 8q. The common intervals of chromosomal imbalance have been narrowed down using array-comparative genomic hybridization (CGH). However, the chromosomal intervals still contain many genes potentially involved in MCL pathogeny. Combined analysis of tiling-resolution array-CGH with gene expression profiling on 11 MCL tumours enabled the identification of genomic alterations and their corresponding gene expression profiles. Only subsets of genes located within given cytogenetic anomaly-intervals showed a concomitant change in mRNA expression level. The genes that showed consistent correlation between DNA copy number and RNA expression levels are likely to be important in MCL pathology. Besides several ,anonymous genes', we also identified various fully annotated genes, whose gene products are involved in cyclic adenosine monophosphate-regulated pathways (PRKACB), DNA damage repair, maintenance of chromosome stability and prevention of rereplication (ATM, ERCC5, FBXO5), energy metabolism (such as genes that are involved in the synthesis of proteins encoded by the mitochondrial genome) and signal transduction (ARHGAP29). Deregulation of these gene products may interfere with the signalling pathways that are involved in MCL tumour development and maintenance. [source] Fluorescence in situ hybridization for detecting genomic alterations of cyclin D1 and p16 in oral squamous cell carcinomasCANCER, Issue 10 2007Narikazu Uzawa DDS Abstract BACKGROUND Cyclin D1 (CCND1) and p16 alterations have been detected in oral squamous cell carcinomas (SCCs), suggesting that abnormalities of these genes may play an important role in the genesis or progression of oral SCCs and serve as independent prognostic indicators. The detection of CCND1 and p16 aberrations using a simple and sensitive method would be valuable for the development of effective treatment modalities for oral cancer. The objective of the current study was to determine whether CCND1 numerical aberrations and p16 deletions in oral SCCs detected by fluorescence in situ hybridization (FISH) have any impact on clinical outcome. METHODS Using genomic DNA probes for CCND1 and p16, FISH was performed on specimens that were obtained by fine-needle aspiration (FNA) from 57 primary oral SCCs. RESULTS The CCND1 numerical aberration was observed in 28 of 57 patients (49%) with oral SCCs and was associated significantly with reduced disease-free survival (P = .0004) and overall survival (P = .0179). Conversely, p16 deletion was detected in 22 of 57 patients (39%). The disease-free and overall survival rates for patients with p16 deletion were lower than those among patients without the p16 deletion, although the difference just failed to reach statistical significance (P = .0516 and P = .1878, respectively). The p16 deletion in the presence of the CCND1 numerical aberration conferred significantly worse disease-free survival (P = .0002) and overall survival (P = .0153). CONCLUSIONS Although the CCND1 numerical aberration was a good predictor of aggressive tumors, recurrence, and poor prognosis in patients with oral SCCs, the authors were able to identify subgroups of patients that had early disease recurrence and a poor prognosis more efficiently by assessment of p16 deletion in addition to CCND1 genetic status using FISH on FNA biopsy samples compared with the analysis of either alteration alone. Cancer 2007. © 2007 American Cancer Society. [source] | |||||||||||||||||||||||||