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Mutational profiling of acute myeloid leukemia with normal cytogenetics in Brazilian patients: the value of next-generation sequencing for genomic classification

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JOURNAL OF INVESTIGATIVE MEDICINE 2017年第8期65卷 1155-1158页

作者： de Noronha, Thiago Rodrigo Mitne-Neto, Miguel Chauffaille, Maria de Lourdes Univ Fed Sao Paulo Div Hematol BR-4037002 Sao Paulo Brazil Fleury Grp Res & Dev Sao Paulo Brazil

Karyotype (KT) aberrations are important prognostic factors for acute myeloid leukemia (AML);however, around 50% of cases present normal results. single nucleotide polymorphism array can detect chromosomal gains, losses or uniparental disomy that are invisible to KT, thus improving patients' risk assessment. However, when both tests are normal, important driver mutations can be detected by the use of next-generation sequencing (NGS). Fourteen adult patients with AML with normal cytogenetics were investigated by NGS for 19 AML-related genes. Every patient presented at least one mutation: DNMT3A in nine patients;IDH2 in six;IDH1 in three;NRAS and NPM1 in two;and TET2, ASXL1, PTPN11, and RUNX1 in one patient. No mutations were found in FLT3, KIT, JAK2, CEBPA, GATA2, TP53, BRAF, CBL, KRAS, and WT1 genes. Twelve patients (86%) had at least one mutation in genes related with DNA methylation (DNMT3A, IDH1, IDH2, and TET2), which is involved in regulation of gene expression and genomic stability. All patients could be reclassified based on genomic status and nine had their prognosis modified. In summary, NGS offers insights into the molecular pathogenesis and biology of cytogenetically normal AML in Brazilian patients, indicating that the prognosis could be further stratified by different mutation combinations. This study shows a different frequency of mutations in Brazilian population that should be confirmed.

关键词： acute myeloid leukemia cytogenetically normal single nucleotide polymorphism array targeted next generation sequencing

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Landscape of somatic allelic imbalances and copy number alterations in HER2-amplified breast cancer

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BREAST CANCER RESEARCH 2011年第6期13卷 1-15页

作者： Staaf, Johan Jonsson, Goran Ringner, Markus Baldetorp, Bo Borg, Ake Lund Univ Dept Oncol SE-22185 Lund Sweden Skane Univ Hosp SE-22185 Lund Sweden Lund Univ CREATE Hlth Strateg Ctr Translat Canc Res SE-22184 Lund Sweden Lund Univ Biomed Ctr Lund Strateg Res Ctr Stem Cell Biol & Cell Therap SE-22184 Lund Sweden

Introduction: Human epidermal growth factor receptor 2 (HER2)-amplified breast cancer represents a clinically well-defined subgroup due to availability of targeted treatment. However, HER2-amplified tumors have been shown to be heterogeneous at the genomic level by genome-wide microarray analyses, pointing towards a need of further investigations for identification of recurrent copy number alterations and delineation of patterns of allelic imbalance. Methods: High-density whole genome array-based comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) array data from 260 HER2-amplified breast tumors or cell lines, and 346 HER2-negative breast cancers with molecular subtype information were assembled from different repositories. Copy number alteration (CNA), loss-of-heterozygosity (LOH), copy number neutral allelic imbalance (CNN-AI), subclonal CNA and patterns of tumor DNA ploidy were analyzed using bioinformatical methods such as genomic identification of significant targets in cancer (GISTIC) and genome alteration print (GAP). The patterns of tumor ploidy were confirmed in 338 unrelated breast cancers analyzed by DNA flow cytometry with concurrent BAC aCGH and gene expression data. Results: A core set of 36 genomic regions commonly affected by copy number gain or loss was identified by integrating results with a previous study, together comprising > 400 HER2-amplified tumors. While CNN-AI frequency appeared evenly distributed over chromosomes in HER2-amplified tumors, not targeting specific regions and often < 20% in frequency, the occurrence of LOH was strongly associated with regions of copy number loss. HER2-amplified and HER2-negative tumors stratified by molecular subtypes displayed different patterns of LOH and CNN-AI, with basal-like tumors showing highest frequencies followed by HER2-amplified and luminal B cases. Tumor aneuploidy was strongly associated with increasing levels of LOH, CNN-AI, CNAs and occurrence of subclonal copy

关键词： Breast Cancer single nucleotide polymorphism array Copy Number Loss PAM50 Subtype Tumor Ploidy

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Maternally inherited deletion encompassing the RTL1as and MEG8 genes of the human 14q32 imprinted region in a patient with a mild Kagami-Ogata syndrome phenotype

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AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2023年第8期191卷 2225-2231页

作者： Sirera, Paula Sirera Garcia-Paya, Elena Garcia, Julia Olivas Rodriguez, Rocio Jadraque Romero, Sofia Daniela Hernandez Hosp Gen Univ Dr Balmis Alicante Lab Mol Cytogenet Inst Invest Sanitaria & Biomed Alicante ISABIAL Alicante Spain Hosp Gen Univ Dr Balmis Alicante Dept Pediat Inst Invest Sanitaria & Biomed Alicante ISABIAL Alicante Spain

Kagami-Ogata syndrome and Temple syndrome are imprinting disorders caused by the abnormal expression of genes in an imprinted cluster on chromosome 14q32. Here, we report a female with mild features of the Kagami-Ogata syndrome phenotype with polyhydramnios, neonatal hypotonia, feeding difficulties, abnormal foot morphology, patent foramen ovale, distal arthrogryposis, normal facial profile, and a bell-shaped thorax without coat hanger ribs. The single nucleotide polymorphism array revealed the interstitial deletion of chromosome 14q32.2-q32.31 (117 kb in size), involving the RTL1as and MEG8 genes, and other small nucleolar RNAs and microRNAs. The differentially methylated regions (DMRs) appeared unaltered. The RTL1as gene deletion and the normal methylation pattern of the MEG3 gene loci were confirmed by methylation-specific multiplex ligation-dependent probe amplification. Deletions of the 14q32 region without involving DMRs, and encompassing only the RTL1as and MEG8 genes, are poorly described in the literature. The mother's chromosomal microarray also confirmed the identical 14q32.2 deletion, although she presented a normal phenotype. The maternally inherited 14q32 deletion was responsible for Kagami-Ogata syndrome in our patient. It was not sufficient, however, to produce Temple syndrome or any other pathogenic phenotype in the patient's mother.

关键词： deletion Kagami-Ogata syndrome maternally inherited 14q32 deletion MEG8 gene RTL1as gene single nucleotide polymorphism array

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Copy number variation and genomic alterations in health and disease

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GENOME MEDICINE 2009年第2期1卷 1-4页

作者： Patrinos, George P. Petersen, Michael B. Erasmus MC Dept Cell Biol & Genet Ctr Med Genet Fac Med & Hlth Sci NL-3000 CA Rotterdam Netherlands Univ Patras Fac Hlth Sci Dept Pharm GR-26504 Patras Greece Inst Child Hlth Dept Genet Athens 11526 Greece

A report of the 1st GOLDEN HELIX Symposium 'Copy number variation and genomic alterations in health and disease', Athens, Greece, 28-29 November 2008.

关键词： Autism Spectrum Disorder Copy Number Variation single nucleotide polymorphism array Charge Syndrome Wellcome Trust Sanger Institute

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Interpretation of custom designed Illumina genotype cluster plots for targeted association studies and next-generation sequence validation

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BMC Research Notes 2010年第1期3卷 1-6页

作者： Tindall, Elizabeth A Petersen, Desiree C Nikolaysen, Stina Miller, Webb Schuster, Stephan C Hayes, Vanessa M Cancer Genetics Group Children's Cancer Institute Australia for Medical Research Sydney Children's Hospital Randwick NSW 2031 High Street Australia Faculty of Medicine University of New South Wales Randwick NSW 2031 Australia Faculty of Science University of New South Wales Randwick NSW 2031 Australia Pennsylvania State University Center for Comparative Genomics and Bioinformatics University Park PA 16802 United States

Background. High-throughput custom designed genotyping arrays are a valuable resource for biologically focused research studies and increasingly for validation of variation predicted by next-generation sequencing (NGS) technologies. We investigate the Illumina GoldenGate chemistry using custom designed VeraCode and sentrix array matrix (SAM) assays for each of these applications, respectively. We highlight applications for interpretation of Illumina generated genotype cluster plots to maximise data inclusion and reduce genotyping errors. Findings. We illustrate the dramatic effect of outliers in genotype calling and data interpretation, as well as suggest simple means to avoid genotyping errors. Furthermore we present this platform as a successful method for two-cluster rare or non-autosomal variant calling. The success of high-throughput technologies to accurately call rare variants will become an essential feature for future association studies. Finally, we highlight additional advantages of the Illumina GoldenGate chemistry in generating unusually segregated cluster plots that identify potential NGS generated sequencing error resulting from minimal coverage. Conclusions. We demonstrate the importance of visually inspecting genotype cluster plots generated by the Illumina software and issue warnings regarding commonly accepted quality control parameters. In addition to suggesting applications to minimise data exclusion, we propose that the Illumina cluster plots may be helpful in identifying potential in-put sequence errors, particularly important for studies to validate NGS generated variation. © 2010 Hayes et al;licensee BioMed Central Ltd.

关键词： Minimal Coverage single nucleotide polymorphism array Tasmanian Devil Allele Specific Oligo single nucleotide polymorphism Assay

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Laser capture microdissection (LCM) and whole genome amplification (WGA) of DNA from normal breast tissue - Optimization for genome wide array analyses

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BMC Research Notes 2011年第1期4卷 1-7页

作者： Aaltonen, Kristina E. Ebbesson, Anna Wigerup, Caroline Hedenfalk, Ingrid Department of Oncology Clinical Sciences Lund Lund University Barngatan 2B Lund SE-221 85 Sweden Department of Laboratory Medicine Center for Molecular Pathology Lund University University Hospital MAS Malmö SE-20502 Sweden

Background: Laser capture microdissection (LCM) can be applied to tissues where cells of interest are distinguishable from surrounding cell populations. Here, we have optimized LCM for fresh frozen normal breast tissue where large amounts of fat can cause problems during microdissection. Since the amount of DNA needed for genome wide analyses, such as single nucleotide polymorphism (SNP) arrays, is often greater than what can be obtained from the dissected tissue, we have compared three different whole genome amplification (WGA) kits for amplification of DNA from LCM material. In addition, the genome wide profiling methods commonly used today require extremely high DNA quality compared to PCR based techniques and DNA quality is thus critical for successful downstream analyses. Findings: We found that by using FrameSlides without glass backing for LCM and treating the slides with acetone after staining, the problems caused by excessive fat could be significantly decreased. The amount of DNA obtained after extraction from LCM tissue was not sufficient for direct SNP array analysis in our material. However, the two WGA kits based on Phi29 polymerase technology (Repli-g^® (Qiagen) and GenomiPhi (GE Healthcare)) gave relatively long amplification products, and amplified DNA from Repli-g^® gave call rates in the subsequent SNP analysis close to those from non-amplified DNA. Furthermore, the quality of the input DNA for WGA was found to be essential for successful SNP array results and initial DNA fragmentation problems could be reduced by switching from a regular halogen lamp to a VIS-LED lamp during LCM. Conclusions: LCM must be optimized to work satisfactorily in difficult tissues. We describe a work flow for fresh frozen normal breast tissue where fat is inclined to cause problems if sample treatment is not adapted to this tissue. We also show that the Phi29-based Repli-g^® WGA kit (Qiagen) is a feasible approach to amplify DNA of high qua

关键词： Normal Breast Tissue Laser Capture Microdissection single nucleotide polymorphism array Whole Genome Amplification Multiple Displacement Amplification

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Genomic study of the response of chicken to highly pathogenic avian influenza virus

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BMC Proceedings 2011年第4期5卷 1-4页

作者： Sironi, Laura Williams, John L. Stella, Alessandra Minozzi, Giulietta Moreno, Ana Ramelli, Paola Han, Jianlin Weigend, Steffen Wan, Junxing Lombardi, Guerino Cordioli, Paolo Mariani, Paola Parco Tecnologico Padano Lodi 26900 Italy Animal Health Department Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna Bruno Ubertini Brescia 25124 Italy CAAS-ILRI Joint Laboratory on Livestock and Forage Genetic Resources Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS) Beijing 100193 China Institute of Farm Animal Genetics Friedrich Loeffler Institut Mariensee D-31535 Germany DIPAV Università degli Studi di Milano Milano 20133 Italy IBBACNR Lodi 26900 Italy

Background: The host mounts an immune response to pathogens, but few data are currently available on the role of host genetics in variation in response to avian influenza (AI). The study presented here investigated the role of the host genetic background in response to in vivo infection with AI virus (AIV). Methods: Experimental lines of chicken and commercial crosses were experimentally infected intratracheally with 10³ EID₅₀/bird of A/Chicken/Italy/13474/99 H7N1 highly pathogenic avian influenza virus (HPAIV). Chickens were genotyped for the Mx polymorphism causing the S631N mutation, and for the Major Histocompatibility Complex (MHC). Whole-genome genotyping was carried out using 60 k single nucleotide polymorphism (SNP) array developed by the poultry Genome-Wide Marker-Assisted Selection Consortium (GWMASC). Results: Variability in response of different chicken lines to the HPAIV infections and some degree of resistance to AI were observed: a statistically significant effect of chicken line on the response to infection was found. There was no association between survival in healthy conditions and polymorphisms at the Mx gene and the MHC-B region. The analysis based on the 60 k SNPs provided a good clustering of the chicken lines, but no specific genetic cluster associated with response to AIV was identified. Conclusions: Neither the genotype at the Mx gene or MHC-B locus, nor for SNP spanning the whole-genome identified loci involved in variations to response to AIV infection. These results point towards the possibility that either the genetic factors affecting the response of chickens to the H7N1 HPAIV are weak, or relevant alleles were not segregating in the studied populations. © 2011 Sironi et al;licensee BioMed Central Ltd.

关键词： Major Histocompatibility Complex Avian Influenza single nucleotide polymorphism array Highly Pathogenic Avian Influenza Virus Chicken Line

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Small Intestinal Neuroendocrine Tumor: A Rare Malignancy with Favorable Outcome

Small Intestinal Neuroendocrine Tumor: A Rare Malignancy wit...

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作者： OLOV NORLEN Uppsala University

学位级别：博士

Small intestinal neuroendocrine tumor (SI-NET) is the most common small bowel tumor in Europe and USA, with an annual incidence of around 0.3-1.3/100000 persons. SI-NETs are the most common type of gastroenteropancreatic NETs (GEP-NETs), and they are known for their ability to produce hormones such as tachykinins and serotonin, as well as for their favorable long-term prognosis in comparison to gastrointestinal adenocarcinoma. The overall aim of the thesis was to investigate unknown or unclear aspects of SI-NET disease, in connection with prognosis, treatment and follow-up. Paper I confirmed several known negative prognostic factors and also showed, for the first time, that para-aortal lymph node metastases and peritoneal carcinomatosis were associated with worse survival by multivariable analyses. Locoregional surgery was associated with a low post-operative mortality, and a prolonged long-term survival by multivariable analysis. In Paper II we continued to investigate peritoneal carcinomatosis and found it be a risk factor not only for death, but also for emergency re-surgery. Furthermore, genetic analyses of samples from primary tumors in patients with and without peritoneal carcinomatosis showed a difference in the DNA between these two groups. In Paper III the outcome after liver surgery and/or radiofrequency ablation of liver metastases was investigated. To summarize, no difference in survival was seen in patients treated with surgery/radiofrequency ablation in comparison with matched controls. However, a superior radiological response of liver metasases and lower U-5-HIAA values were seen in patients subjected to liver surgery and/ or radiofrequency ablation compared to matched controls. Paper IV compared ultrasonography, computed tomography and 11 C-5HTP-PET in the follow-up after radiofrequency ablation of NET liver metastases. The study concluded that 11 C-5HTP-PET depicted all residual tumors after RFA and that it, if used, should be combined with compute

关键词： Neuroendocrine tumor peritoneal carcinomatosis single nucleotide polymorphism array liver metastases radiofrequency ablation liver surgery positron emission tomography somatostatin analogs cholecystectomy

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Analysis and visualization of chromosomal abnormalities in SNP data with SNPscan

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BMC BIOINFORMATICS 2006年第1期7卷 25-25页

作者： Ting, JC Ye, Y Thomas, GH Ruczinski, I Pevsner, J Kennedy Krieger Inst Dept Neurol Baltimore MD 21205 USA Johns Hopkins Sch Med Pathobiol Grad Program Baltimore MD 21205 USA Johns Hopkins Sch Med Dept Pediat Baltimore MD 21205 USA Johns Hopkins Sch Med Dept Pathol Baltimore MD 21205 USA Kennedy Krieger Inst Dept Genet Baltimore MD 21205 USA Johns Hopkins Bloomberg Sch Publ Hlth Dept Biostat Baltimore MD 21205 USA Johns Hopkins Sch Med Dept Neurosci Baltimore MD 21205 USA

Background: A variety of diseases are caused by chromosomal abnormalities such as aneuploidies ( having an abnormal number of chromosomes), microdeletions, microduplications, and uniparental disomy. High density single nucleotide polymorphism (SNP) microarrays provide information on chromosomal copy number changes, as well as genotype ( heterozygosity and homozygosity). SNP array studies generate multiple types of data for each SNP site, some with more than 100,000 SNPs represented on each array. The identification of different classes of anomalies within SNP data has been challenging. Results: We have developed SNPscan, a web-accessible tool to analyze and visualize high density SNP data. It enables researchers ( 1) to visually and quantitatively assess the quality of user-generated SNP data relative to a benchmark data set derived from a control population, ( 2) to display SNP intensity and allelic call data in order to detect chromosomal copy number anomalies ( duplications and deletions), ( 3) to display uniparental isodisomy based on loss of heterozygosity (LOH) across genomic regions, ( 4) to compare paired samples ( e. g. tumor and normal), and ( 5) to generate a file type for viewing SNP data in the University of California, Santa Cruz (UCSC) Human Genome Browser. SNPscan accepts data exported from Affymetrix Copy Number Analysis Tool as its input. We validated SNPscan using data generated from patients with known deletions, duplications, and uniparental disomy. We also inspected previously generated SNP data from 90 apparently normal individuals from the Centre d'Etude du polymorphisme Humain ( CEPH) collection, and identified three cases of uniparental isodisomy, four females having an apparently mosaic X chromosome, two mislabelled SNP data sets, and one microdeletion on chromosome 2 with mosaicism from an apparently normal female. These previously unrecognized abnormalities were all detected using SNPscan. The microdeletion was independently confirmed by

关键词： Copy Number Change single nucleotide polymorphism array Portable Document Format single nucleotide polymorphism Data Portable Network Graphic

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Comparison of genotype clustering tools with rare variants

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BMC BIOINFORMATICS 2014年第1期15卷 1-12页

作者： Perreault, Louis-Philippe Lemieux Legault, Marc-Andre Barhdadi, Amina Provost, Sylvie Normand, Valerie Tardif, Jean-Claude Dube, Marie-Pierre Beaulieu Saucier Univ Montreal Pharmacogen Ctr Montreal Heart Inst Res Ctr Montreal PQ Canada Univ Montreal Fac Med Montreal PQ H3C 3J7 Canada

Background: Along with the improvement of high throughput sequencing technologies, the genetics community is showing marked interest for the rare variants/common diseases hypothesis. While sequencing can still be prohibitive for large studies, commercially available genotyping arrays targeting rare variants prove to be a reasonable alternative. A technical challenge of array based methods is the task of deriving genotype classes (homozygous or heterozygous) by clustering intensity data points. The performance of clustering tools for common polymorphisms is well established, while their performance when conducted with a large proportion of rare variants (where data points are sparse for genotypes containing the rare allele) is less known. We have compared the performance of four clustering tools (GenCall, GenoSNP, optiCall and zCall) for the genotyping of over 10,000 samples using the Illumina's HumanExome BeadChip, which includes 247,870 variants, 90% of which have a minor allele frequency below 5% in a population of European ancestry. Different reference parameters for GenCall and different initial parameters for GenoSNP were tested. Genotyping accuracy was assessed using data from the 1000 Genomes Project as a gold standard, and agreement between tools was measured. Results: Concordance of GenoSNP's calls with the gold standard was below expectations and was increased by changing the tool's initial parameters. While the four tools provided concordance with the gold standard above 99% for common alleles, some of them performed poorly for rare alleles. The reproducibility of genotype calls for each tool was assessed using experimental duplicates which provided concordance rates above 99%. The inter-tool agreement of genotype calls was high for approximately 95% of variants. Most tools yielded similar error rates (approximately 0.02), except for zCall which performed better with a 0.00164 mean error rate. Conclusions: The GenoSNP clustering tool could not be run stra

关键词： Rare Variant Rare Allele single nucleotide polymorphism array Cluster Tool Genotype Cluster

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