Deregulation of the EGFR signaling pathway is one of the most frequently observed genetic abnormalities that drives cancer development. Although mutations in the downstream components of the EGFR signaling pathway, including KRAS, BRAF and PIK3CA, have been reported in numerous cancers, extensive mutation and copy number analysis of these genes in clinical samples has not been performed for head and neck squamous cell carcinoma (HNSCC). We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients. We used DNA sequencing to detect mutations and the copy number changes were evaluated by qPCR and array comparative genomic hybridization (CGH) analysis. We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients. We identified 3 mutations (2.6%) in K-RAS and 3 mutations (2.6%) in PIK3CA. Copy number amplification was
The extent to which large duplications and deletions contribute to human genetic variation and diversity is unknown. Here, we show that large-scale copy number polymorphisms (CNPs) (about 100 kilobases and greater) contribute substantially to genomic variation between normal humans. Representational oligonucleotide microarray analysis of 20 individuals revealed a total of 221 copy number differences representing 76 unique CNPs. On average, individuals differed by 11 CNPs, and the average length of a CNP interval was 465 kilobases. We observed copy number variation of 70 different genes within CNP intervals, including genes involved in neurological function, regulation of cell growth, regulation of metabolism, and several genes known to be associated with disease.. ...
Changes in gene and chromosome copy number are widely observed in systems from cancer to drug resistance to genome evolution. Despite the importance of aneuploi...
Rasmussen M, Sundström M, Göransson Kultima H, Botling J, Micke P, Birgisson H, Glimelius B, Isaksson A Genome Biol. 12 (10) R108 [2011-10-24; online 2011-10-24] We describe a bioinformatic tool, Tumor Aberration Prediction Suite (TAPS), for the identification of allele-specific copy numbers in tumor samples using data from Affymetrix SNP arrays. It includes detailed visualization of genomic segment characteristics and iterative pattern recognition for copy number identification, and does not require patient-matched normal samples. TAPS can be used to identify chromosomal aberrations with high sensitivity even when the proportion of tumor cells is as low as 30%. Analysis of cancer samples indicates that TAPS is well suited to investigate samples with aneuploidy and tumor heterogeneity, which is commonly found in many types of solid tumors. Affiliated researcher QC bibliography QC xrefs PubMed 22023820. DOI 10.1186/gb-2011-12-10-r108. Crossref 10.1186/gb-2011-12-10-r108. ...
DNA copy number alterations in 146 bladder tumors.A) Whole genome heatmap representing relative copy number profiles of the samples. Segments of gains or deleti
TY - JOUR. T1 - A versatile statistical analysis algorithm to detect genome copy number variation. AU - Daruwala, Raoul Sam. AU - Rudra, Archisman. AU - Ostrer, Harry. AU - Lucito, Robert. AU - Wigler, Michael. AU - Mishra, Bud. PY - 2004/11/16. Y1 - 2004/11/16. N2 - We have developed a versatile statistical analysis algorithm for the detection of genomic aberrations in human cancer cell lines. The algorithm analyzes genomic data obtained from a variety of array technologies, such as oligonucleotide array, bacterial artificial chromosome array, or array-based comparative genomic hybridization, that operate by hybridizing with genomic material obtained from cancer and normal cells and allow detection of regions of the genome with altered copy number. The number of probes (i.e., resolution), the amount of uncharacterized noise per probe, and the severity of chromosomal aberrations per chromosomal region may vary with the underlying technology, biological sample, and sample preparation. Constrained ...
Complement component 4 (C4) gene copy number (GCN) affects the susceptibility to systemic lupus erythematosus (SLE) in different populations, however the possible phenotype significance remains to be determined. This study aimed to associate C4A, C4B and total C4 GCN and SLE, focusing on the clinical phenotype and disease progression. C4, C4A and C4B GCN were determined by real-time PCR in 427 SLE patients and 301 healthy controls, which underwent a detailed clinical evaluation according to a pre-established protocol. The risk of developing SLE was 2.62 times higher in subjects with low total C4 GCN (| 4 copies, OR = 2.62, CI = 1.77 to 3.87, p | 0.001) and 3.59 times higher in subjects with low C4A GCN (| 2 copies; OR = 3.59, CI = 2.15 to 5.99, p | 0.001) compared to those subjects with normal or high GCN of total C4 (≥4) and C4A (≥2), respectively. An increased risk was also observed regarding low C4B GCN, albeit to a lesser degree (OR = 1.46, CI = 1.03 to 2.08, p = 0.03). Furthermore, subjects
Diagnosing constitutional pathogenic copy number variants (CNVs) requires detecting submicroscopic segmental chromosomal imbalances
Sequencing technology is increasingly demonstrating the impact of genomic copy number variation (CNV) on phenotypes. Opposing variation in growth, head size, cognition and behaviour is known to result from deletions and reciprocal duplications of some genomic regions. We propose normative inversion of face shape, opposing difference from a matched norm, as a basis for investigating the effects of gene dosage on craniofacial development. We use dense surface modelling techniques to match any face (or part of a face) to a facial norm of unaffected individuals of matched age, sex and ethnicity and then we reverse the individuals face shape differences from the matched norm to produce the normative inversion. We demonstrate for five genomic regions, 4p16.3, 7q11.23, 11p15, 16p13.3 and 17p11.2, that such inversion for individuals with a duplication or (epi)-mutation produces facial forms remarkably similar to those associated with a deletion or opposite (epi-)mutation of the same region, and vice versa. The
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Identifying genetic cues of functional relevance is key to understanding the drivers of evolution and increasingly important for the conservation of biodiversity. This study introduces nuclear ribosomal DNA (nrDNA) to mitochondrial DNA (mtDNA) copy number ratios as a metric with which to screen for this functional genetic variation prior to more extensive omics analyses. To illustrate the metric, quantitative PCR was used to estimate nrDNA (18S) to mtDNA (16S) copy number ratios in muscle tissue from samples of two zooplankton species: Salpa thompsoni caught near Elephant Island (Southern Ocean) and S. fusiformis sampled off Gough Island (South Atlantic). Average 18S:16S ratios in these samples were 9:1 and 3:1, respectively. nrDNA 45S arrays and mitochondrial genomes were then deep sequenced to uncover the sources of intra-individual genetic variation underlying these 18S:16S copy number differences. The deep sequencing profiles obtained were consistent with genetic changes resulting from ...
Importantly, when creating the mimicked data sets we did not generate any simulated ratio values; rather, we formed different selections of values using real experimental data. We believe that this use of real experimental data is of significance for aCGH data. This belief is founded on that, in contrast to expression levels, copy number levels are restricted to a, by comparison, moderate dynamic range. Therefore, when a genomic region is subjected to gain or amplification, the increase of genomic material is relatively substantial. Thus, we reasoned that probes for regions of gain would yield comparably higher average intensities than those for regions of normal copy number and that this, in turn, would result in a correlation between M and A: probes measuring ratios of gain will have higher average intensities. The opposite relationship would apply for probes measuring ratios of loss. Consequently, utilizing normalization strategies based on Lowess would possibly correct for correlations ...
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A research team led by Associate Professor Jonathan Sebat, Ph.D., of Cold Spring Harbor Laboratory (CSHL) has developed a sensitive and accurate way of identifying gene copy number variations (CNVs). The method, which is ...
Large deletions encompassing the NF1 gene and its flanking regions belong to the group of genomic disorders caused by copy number changes that are mediated by the local genomic architecture. Although nonallelic homologous recombination (NAHR) is known to be a major mutational mechanism underlying such genomic copy number changes, the sequence determinants of NAHR location and frequency are still poorly understood since few high-resolution mapping studies of NAHR hotspots have been performed to date. Here, we have characterized two NAHR hotspots, PRS1 and PRS2, separated by 20 kb and located within the low-copy repeats NF1-REPa and NF1-REPc, which flank the human NF1 gene region. High-resolution mapping of the crossover sites identified in 78 type 1 NF1 deletions mediated by NAHR indicated that PRS2 is a much stronger NAHR hotspot than PRS1 since 80% of these deletions exhibited crossovers within PRS2, whereas 20% had crossovers within PRS1. The identification of the most common strand exchange ...
Purpose: As genome-scale technologies begin to unravel the complexity of the equivalent tumors in adults, we can attempt detailed characterization of high-grade gliomas in children, that have until recently been lacking. Toward this end, we sought to validate and extend investigations of the differences between pediatric and adult tumors.. Experimental Design: We carried out copy number profiling by array comparative genomic hybridization using a 32K bacterial artificial chromosome platform on 63 formalin-fixed paraffin-embedded cases of high-grade glioma arising in children and young people (,23 years).. Results: The genomic profiles of these tumors could be subclassified into four categories: those with stable genomes, which were associated with a better prognosis; those with aneuploid and those with highly rearranged genomes; and those with an amplifier genotype, which had a significantly worse clinical outcome. Independent of this was a clear segregation of cases with 1q gain (more common in ...
View article as PDF. In recent years, we have dramatically changed our view of human genome, from a collection of DNA base pairs that was largely quite stable to one whose very structure can change. Weve learned that higher-order structural features, such as specific configurations of repeated base pair sequences, can predispose for DNA rearrangements.1. One of the most intriguing types of DNA rearrangements is copy-number variants (CNVs), deletions or duplications of parts of the genome. While CNVs range in size from a few hundred base pairs to several mega-bases affecting the copy number of one to dozens of juxtaposed genes, they are not identifiable by conventional light microscopy. It was not until a few years ago that improved technology enabled us to perform high-resolution genome-wide surveys of CNVs in individual genomes. These surveys revealed a large amount of copy number variation (at least 12,000 CNVs overlapping more than 1,000 genes), most of which represent benign polymorphic ...
4468 Detecting the genetic changes associated with cancer development and progression is a major focus in current cancer research. We have developed a high-resolution technology to assess DNA copy number changes in cancer and other diseases. The method combines our whole genome sampling analysis (WGSA), which genotypes over 100,000 single nucleotide polymorphisms (SNPs) from nanogram quantities of human genomic DNA, and our chromosomal copy number tool (CCNT). CCNT can detect regions of chromosomal deletion, amplification, and loss of heterozygosity (LOH). Copy number changes are calculated based on SNP hybridization signal intensity data from the experimental sample relative to intensity distributions derived from a reference set containing over 100 individuals. CCNT also provides a statistical significance of this intensity difference. Several advantages of this technique include the simultaneous collection of genotype information and DNA copy number changes, no requirement of a reference ...
MYC copy gain, chromosomal instability and PI3K activation as potential markers of unfavourable outcome in trastuzumab-treated patients with metastatic breast cancer. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Purpose: The expression of HAGE as a novel prognostic and predictive tool was assessed in 1079 TNBCs. Experimental Design: HAGE protein expression was investigated in an early primary TNBC (EP-TNBC; n=520) cohort who received adjuvant chemotherapy (ACT) and in a locally advanced primary TNBC cohort who received anthracycline-combination Neo-ACT (n=110; AC-Neo-ACT). HAGE-mRNA expression was evaluated in the METABRIC-TNBC-cohort (n=311) who received ACT and in a cohort of patients with TNBC who received doxorubicin/cyclophosphamide Neo-ACT, followed by 1:1 randomisation to ixabepilone (n=68) or paclitaxel (n=64) as part of a phase II clinical trial. Furthermore, a cohort of 128 tumours with integrated HAGE gene copy number changes, mRNA and protein levels were analysed. Results: In patients with EP-TNBC, who were chemotherapy-naïve, high HAGE protein expression (HAGE+) was associated with a higher risk of death (HR: 1.3; 95% CI: 1.2-1.5; p=0.000005) when compared HAGE- cases. Patients who ...
These results highlight the benefits of using CNstream, a method for whole-genome CNV discovery and genotyping for Illumina BeadChip arrays. The present method combined a single-locus scoring approach that takes advantage of the joint clustering analysis of all the intensity samples at each probe with the computational speed and analytical accuracy of estimating CNPs from segments of consecutive probes. Compared with PennCNV, CNstream has superior sensitivity in several common CNPs and it can identify different CNPs that are not detected by PennCNV. The CNP detected by CNstream was demonstrated to be the most significantly associated with RA susceptibility using available RT-PCR technology.. With regard to the single-locus scoring method, CNstream reduced the processing time by robustly initializing the GMM before the EM procedure. This allows a whole-genome analysis to be carried out without the need for previously defined CNP maps, which are required for the SCIMM method. In addition, in ...
Bioconductor version: Release (3.6) The CINdex package addresses important area of high-throughput genomic analysis. It allows the automated processing and analysis of the experimental DNA copy number data generated by Affymetrix SNP 6.0 arrays or similar high throughput technologies. It calculates the chromosome instability (CIN) index that allows to quantitatively characterize genome-wide DNA copy number alterations as a measure of chromosomal instability. This package calculates not only overall genomic instability, but also instability in terms of copy number gains and losses separately at the chromosome and cytoband level.. Author: Lei Song, Krithika Bhuvaneshwar, Yue Wang, Yuanjian Feng, Ie-Ming Shih, Subha Madhavan, Yuriy Gusev Maintainer: Yuriy Gusev ,yg63 at georgetown.edu, ...
TY - JOUR. T1 - Chromosome 18 gene dosage map 2.0. AU - Cody, Jannine D.. AU - Heard, Patricia. AU - Rupert, David. AU - Hasi-Zogaj, Minire. AU - Hill, Annice. AU - Sebold, Courtney. AU - Hale, Daniel. PY - 2018/12/1. Y1 - 2018/12/1. N2 - In 2009, we described the first generation of the chromosome 18 gene dosage maps. This tool included the annotation of each gene as well as each phenotype associated region. The goal of these annotated genetic maps is to provide clinicians with a tool to appreciate the potential clinical impact of a chromosome 18 deletion or duplication. These maps are continually updated with the most recent and relevant data regarding chromosome 18. Over the course of the past decade, there have also been advances in our understanding of the molecular mechanisms underpinning genetic disease. Therefore, we have updated the maps to more accurately reflect this knowledge. Our Gene Dosage Map 2.0 has expanded from the gene and phenotype maps to also include a pair of maps ...
Dr Liesbeth Lenaerts talks to ecancer at ESMO 2018 about a pre-existing pre-natal test which flagged up copy number alterations and cancer in the foetus'
AbstractLow FCGR3 copy numbers (CNs) has been associated with susceptibility to several systemic autoimmune diseases. However, inconsistent associations were reported and errors caused by shaky methods were suggested to be the major causes. In large scale case control association studies, robust copy number determination method is thus warranted, which was the main focus of the current study. In the present study, FCGR3 CNs of 90 HapMap Asians were firstly checked using four assays including paralogue ratio test combined with restriction enzyme digest variant ratio (PRT-REDVR), real-time quantitative (qPCR) using TaqMan assay, real-time qPCR using SYBR Green dye and short tenden repeat (STR). To improve the comparison precision reproductively, the results were compared with those from recently released sequencing data from 1000 genomes project as well as whole-genome tiling BAC array data. The tendencies of inconsistent samples by these methods were also characterized. Refined in-home TaqMan qPCR assay
Faster implementation of CRLMM specific to SNP 5.0 and 6.0 arrays, as well as a copy number tool specific to 5.0, 6.0, and Illumina platforms.
Molecular Cloning, also known as Maniatis, has served as the foundation of technical expertise in labs worldwide for 30 years. No other manual has been so popular, or so influential.
Are you proposing a thought experiment in which we subtract all the repeat derived sequences (minus the small proportion of bases that regulate gene expression), and most of the the non regulatory intergenic sequences, reducing intron and intergenic sizes by, say 90%, such that we end up with a small number of short chromosomes (say 50 Mb in size - since we know the current division processes can cope with such a size) but keeping the necessary telomeric and centromeric repeats. This would be done with all members of the human species such that all the current copy number polymorphisms and regulatory snps are maintained and all genes are allowed up to 2000bp of regulatory sequences (although we will allow a proportion of genes to have larger regulatory regions). The ultimate result is a human genome that is say, 90% smaller than the current one. You suggest that the current cellular machinery would be able to cope with this change, such that there would be no viability or evolutionary ...
Heterokaryons provide a model system in which to examine how tissue-specific phenotypes arise and are maintained. When muscle cells are fused with nonmuscle cells, muscle gene expression is activated in the nonmuscle cell type. Gene expression was studied either at a single cell level with monoclonal antibodies or in mass cultures at a biochemical and molecular level. In all of the nonmuscle cell types tested, including representatives of different embryonic lineages, phenotypes, and developmental stages, muscle gene expression was induced. Differences among cell types in the kinetics, frequency, and gene dosage requirements for gene expression provide clues to the underlying regulatory mechanisms. These results show that the expression of genes in the nuclei of differentiated cells is remarkably plastic and susceptible to modulation by the cytoplasm. The isolation of the genes encoding the tissue-specific trans-acting regulators responsible for muscle gene activation should now be possible. ...
(A) Standard curve for quantitation of DNA copy number. The vertical axis shows copies of target DNA per reaction. The horizontal axis shows the ct values as de
Autor: Kramer, M. et al.; Genre: Zeitschriftenartikel; Im Druck veröffentlicht: 2010-05-01; Keywords: Paralogs; RAB-like; Gene expression; Paralog ratio test; Pyrosequencing; Titel: Analysis of relative gene dosage and expression differences of the paralogs RABL2A and RABL2B by Pyrosequencing.
Video created by The State University of New York for the course Big Data, Genes, and Medicine. After this module, you will be able to 1. List different types of gene alterations. 2. Compare and contrast methods for detecting gene mutations. 3. ...
Unless it was reslabbed, it is a different copy as the GPA sale you mentioned has a different cert number. It also had light tan - ow pages and was graded in December of 2012. The Ebay listing was graded June of 2016 so it could have been resubbed as all I am going on is the cert number and no scan of the GPA sale ...
Think your method of testing bodyfat is accurate? Youll be surprised to learn the fat-finding facts. Youre dieting & exercising but the numbers on the sca
The recent genome-wide allele-specific copy number variation data enable us to explore two types of genomic information including chromosomal genotype variations as well as DNA copy number variations. For a cancer study, it is common to collect data for paired normal and tumor samples. Then, two types of paired data can be obtained to study a disease subject. However, there is a lack of methods for a simultaneous analysis of these four sequences of data. In this study, we propose a statistical framework based on the change-point analysis approach. The validity and usefulness of our proposed statistical framework are demonstrated through the simulation studies and applications based on an experimental data set.
Copy number analysis usually refers to the process of analyzing data produced by a test for DNA copy number variation in patients sample. Such analysis helps detect chromosomal copy number variation that may cause or may increase risks of various critical disorders. Copy number variation can be detected with various types of tests such as fluorescent in situ hybridization, comparative genomic hybridization and with high-resolution array-based tests based on array comparative genomic hybridization (or aCGH), SNP array technologies and high resolution microarrays that include copy number probes as well an SNPs. Array-based methods have been accepted as the most efficient in terms of their resolution and high-throughput nature and the highest coverage (choose an array with over 2 million probes) and they are also referred to as Virtual Karyotype. Data analysis for an array-based DNA copy number test can be very challenging though due to very high volume of data that come out of an array platform. ...
Recent genome-wide microarray-based research investigations have revealed a high frequency of submicroscopic copy number alterations (CNAs) in the myelodysplastic syndromes (MDS), suggesting microarray-based comparative genomic hybridization (aCGH) has the potential to detect new clinically relevant genomic markers in a diagnostic laboratory. We performed an exploratory study on 30 cases of MDS, myeloproliferative neoplasia (MPN) or evolving acute myeloid leukemia (AML) (% bone marrow blasts ≤ 30%, range 0-30%, median, 8%) by aCGH, using a genome-wide bacterial artificial chromosome (BAC) microarray. The sample data were compared to corresponding cytogenetics, fluorescence in situ hybridization (FISH), and clinical-pathological findings. Previously unidentified imbalances, in particular those considered submicroscopic aberrations (| 10 Mb), were confirmed by FISH analysis. CNAs identified by aCGH were concordant with the cytogenetic/FISH results in 25/30 (83%) of the samples tested. aCGH revealed new
Introduction: Lung cancer, of which 85% is non-small cell (NSCLC), is the leading cause of cancer-related death in the United States. Copy number variations (CNVs) in lung adenocarcinoma do not occur randomly in the genome, but are positionally clustered. However, the functional significance of gene copy number changes remains unclear. We characterized genome-wide copy number profiles in non-small cell lung cancer both positionally and functionally. Methods: A series of 301 tumor samples was collected from NSCLC patients in the Massachusetts General Hospital (MGH), Boston, MA (N=202) and National Institute of Occupational Health in Norway (N=99). Copy numbers were evaluated in genomic DNA extracted from micro-dissected tumor tissue with at least 70% tumor cellularity using dense single nucleotide polymorphism arrays. Inferred copy numbers were obtained with dCHIP, and significance of CNVs for each locus was evaluated with binomial distribution. Gene set enrichment analysis algorithm was used to ...
Background: Congenital malformations are present in approximately 2-3% of liveborn babies and 20% of stillborn fetuses. The mechanisms underlying the majority of sporadic and isolated congenital malformations are poorly understood, although it is hypothesized that the accumulation of rare genetic, genomic and epigenetic variants converge to deregulate developmental networks. Methodology/Principal Findings: We selected samples from 95 fetuses with congenital malformations not ascribed to a specific syndrome (68 with isolated malformations, 27 with multiple malformations). Karyotyping and Multiplex Ligation-dependent Probe Amplification (MLPA) discarded recurrent genomic and cytogenetic rearrangements. DNA extracted from the affected tissue (46%) or from lung or liver (54%) was analyzed by molecular karyotyping. Validations and inheritance were obtained by MLPA. We identified 22 rare copy number variants (CNV) [,100 kb, either absent (n = 7) or very uncommon (n = 15, ,1/2,000) in the control ...
From a number of genome-wide association studies it was shown that de novo and/or rare copy number variants (CNVs) are found at an increased frequency in neuropsychiatric diseases. In this study we examined the prevalence of CNVs in six genomic regions (1q21.1, 2p16.3, 3q29, 15q11.2, 15q13.3, and 16p11.2) previously implicated in neuropsychiatric diseases. Hereto, a cohort of four neuropsychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, and intellectual disability) and control individuals from three different populations was used in combination with Multilpex Amplicon Quantifiaction (MAQ) assays, capable of high resolution (kb range) and custom-tailored CNV detection. Our results confirm the etiological candidacy of the six selected CNV regions for neuropsychiatric diseases. It is possible that CNVs in these regions can result in disturbed brain development and in this way lead to an increased susceptibility for different neuropsychiatric disorders, dependent on ...
Uveal melanomas (UM) are aggressive ocular tumours of adults that are typically characterized by chromosomal aberrations such as loss of 1p, 3, 6q, and gain 6p, and 8q. Of these monosomy 3 (M3) and 8q+ are powerful predictors of prognosis. The relationship of changes affecting chromosome 6 is however more ambivalent, having been linked to both good and poor prognosis, and yet both regions have not been well defined, which suggest the presence of one or more oncogenes in 6p and tumour suppressor gene in 6q. Therefore, different chromosome 6 alterations may have a variable impact on the prognosis of UM, and ultimately contain genes that contribute to the development and metastasis of this disease. It is likely that these changes can act as moderators to the tumour outcome. Although UM disseminates haematogenous with high propensity for the liver, and hepatic involvement reported in over 90% of patients, infrequently some patients will however initially present with metastases in sites other than ...
Mitochondrial dysfunction, generally characterized as a loss of efficiency in oxidative phosphorylation, is a hallmark of aging and a variety of chronic diseases. Mitochondrial dysfunction results in inefficient cellular energy production and in increased levels of reactive oxygen species (ROS) which may damage lipids, proteins, and nucleic acids. Mitochondrial dysfunction also affects the expression of nuclear genes involved in metabolism, growth, differentiation, and apoptosis. All these changes may explain the contribution of mitochondrial dysfunction to chronic and complex human diseases. A major limitation to the routine evaluation of mitochondrial dysfunction in clinical practice is the lack of reliable measures of mitochondrial dysfunction available for clinical use. Mitochondrial DNA copy number (mtDNA-CN) is a promising biomarker of mitochondrial dysfunction that has the potential to become widely available in clinical practice. Other measures of mitochondrial dysfunction, including ...
Abstract: Resistance to chemotherapeutic agents and radiotherapy has kept surgery the primary treatment of uterine leiomyosarcoma (ULMS). In search of leads for potential therapeutic targets, array CGH (aCGH) was used to obtain a genomewide pattern of ULMS-specific genetic imbalances and to define the affected biological processes. Fine-resolution genomewide aCGH analysis was performed using customised 16K cDNA microarrays on 18 primary ULMS cases. Furthermore, patterns of DNA copy number changes were assessed for associations with clinical parameters, i.e., tumour grade, tumour size and patient status at last follow-up. Our aCGH results demonstrated extensive DNA copy number changes in all chromosomes. Of the 10,590 gene loci included in the analysis, 4,387 were found to be affected by DNA copy number gains and 4,518 by DNA copy number losses in at least one case. Further analyses revealed that 231 of these were commonly gained, and 265 lost in at least 20% of the cases. The gains affected loci ...
DNA copy number variants represent the greatest source of genetic variability in humans [1] and are the underlying cause of many human diseases. Array CGH is recognized as a first-tier test for DNA copy number variants (CNV) [2] and accordingly, many laboratories have already established their pipelines for pre-processing of array CGH data and CNV calling. In many cases these pipelines are based on software packages provided by the companies selling DNA microarrays or scanners such as BlueFuse [3], CytoSure [4] or CytoGenomics [5]. Yet, the scope of these tools is focused on the identification of CNVs and their evaluation in the context of gene content and frequency of a given variant in the healthy population. Comparative analysis, which integrates data obtained from multiple patients, or other experiment types are hardly supported, in particular when they are based on different array platforms or NGS technology.. Such kind of meta-analysis needs the implementation of additional commercial or ...
Oncogenic point mutations in KIT or PDGFRA are recognized as the primary events responsible for the pathogenesis of most gastrointestinal stromal tumors (GIST), but additional genomic alterations are frequent and presumably required for tumor progression. The relative contribution of such alterations for the biology and clinical behavior of GIST, however, remains elusive. In the present study, somatic mutations in KIT and PDGFRA were evaluated by direct sequencing analysis in a consecutive series of 80 GIST patients. For a subset of 29 tumors, comparative genomic hybridization was additionally used to screen for chromosome copy number aberrations. Genotype and genomic findings were cross-tabulated and compared with available clinical and follow-up data. We report an overall mutation frequency of 87.5%, with 76.25% of the tumors showing alterations in KIT and 11.25% in PDGFRA. Secondary KIT mutations were additionally found in two of four samples obtained after imatinib treatment. Chromosomal imbalances
About a decade ago the first large catalogs of copy number variants (CNVs) in the human genome were presented [1, 2]. Numerous studies later, CNVs are known to contribute to the genomic variation to a larger extent than single nucleotide polymorphisms (SNPs) in terms of number of nucleotide differences [3, 4]. CNVs are defined as DNA segments of variable length, up to several megabases (Mb), that varies in copy numbers in comparison to a reference genome [5]. The different types of CNVs include deletions and duplications, while consequences of CNVs include e.g. altered gene dosage and regulation, changed gene structure and unmasking of recessive alleles [5]. The effect of CNVs varies from being benign or neutral, to having subtle effects on disease predisposition or directly causing disease. The contribution and importance of CNVs for phenotypic diversity and disease susceptibility has been repeatedly shown in human and several complex diseases such as psoriasis, Crohns disease, type 2 ...
The treatment strategy usually depends on the disease state in the individual patient. However, it is difficult to estimate the disease state before treatment in many patients. The purpose of this study was to develop a BAC (bacterial artificial chromosome) mini-array allowing for the estimation of node metastasis, liver metastasis, peritoneal dissemination and the depth of tumor invasion in gastric cancers. Initially, the DNA copy number aberrations (DCNAs) were analyzed by array-based comparative genomic hybridization (aCGH) in 83 gastric adenocarcinomas as a training-sample set. Next, two independent analytical methods were applied to the aCGH data to identify the BAC clones with DNA copy number aberrations that were linked with the disease states. One of the methods, a decision-tree model classifier, identified 6, 4, 4, 4, and 7 clones for estimating lymph node metastasis, liver metastasis, peritoneal dissemination, depth of tumor invasion, and histological type, respectively. In the other method, a
article{39c3420c-566c-4f24-879b-c3929d10ccd7, abstract = {It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed, significant increased risks of CLL (n=102) with increasing mtDNA ...
Genomic copy number changes are frequently found in cancers and they have been demonstrated to contribute to carcinogenesis; and it is widely accepted that tumors with microsatellite instability (MSI) are genetically stable and mostly diploid. In the present study we compared the copy number alterations and the gene-expression profiles of microsatellite stable (MSS) and MSI colorectal tumors. A total number of 31 fresh-frozen primary tumors (16 MSS and 15 MSI) were used. Twenty-eight samples (15 MSS and 13 MSI) were analyzed with metaphase comparative genomic hybridization (CGH), nine of which plus one additional sample (4 MSS and 6 MSI) were further analyzed by cDNA-based array-CGH. Gene expression analysis was performed with six samples [3 MSS and 3 MSI, four of these used in metaphase CGH (mCGH) analysis] to identify differentially expressed genes possibly located in the lost or amplified regions found by CGH, stressing the biological significance of copy number changes. Metaphase and ...
We conducted a genome-wide scan for large CNVs (≥100 kb) in a case-control dataset of Caribbean Hispanic origin that was previously investigated in a SNP-based GWAS (Lee JH et al. 2010). To generate results with high confidence, we focused on CNVs that were identified by at least two algorithms. We detected 1774 stringent CNVs (Table S4). First, we tested the hypothesis that rare CNVs (≤1%) with a potentially strong impact on AD risk in individual patients might contribute to the overall disease risk, as was previously observed in other common neuropsychiatric disorders (Kirov et al. 2009; Zhang et al. 2009; Glessner et al. 2010). However, the burden analyses of rare CNVs did not find significant differences between cases and controls in CNV rate, total or average CNV size, or the number of genes affected by CNVs.. In addition, we conducted a case-control analysis of large genic CNVs, including common variants, using PLINK regional analysis. The only nominally significant result that ...