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Genome wide SNP comparative analysis between EGFR and KRAS mutated NSCLC and characterization of two models of oncogenic cooperation in non-small cell lung carcinoma

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BMC MEDICAL GENOMICS 2008年第1期1卷 25-25页

作者： Blons, Helene Pallier, Karine Le Corre, Delphine Danel, Claire Tremblay-Gravel, Maxime Houdayer, Claude Fabre-Guillevin, Elizabeth Riquet, Marc Dessen, Philippe Laurent-Puig, Pierre INSERM UMR S775 F-75006 Paris France Univ Paris 05 F-75006 Paris France Hop Europeen Georges Pompidou AP HP Dept Biol F-75015 Paris France Hop Europeen Georges Pompidou AP HP Dept Pathol F-75015 Paris France Inst Curie Dept Mol Oncol F-75005 Paris France Hop Europeen Georges Pompidou AP HP Dept Oncol F-75015 Paris France Hop Europeen Georges Pompidou AP HP Dept Thorac Surg F-75015 Paris France Inst Gustave Roussy Dept Informat F-94905 Villejuif France

Background: Lung cancer with EGFR mutation was shown to be a specific clinical entity. In order to better understand the biology behind this disease we used a genome wide characterization of loss of heterozygosity and amplification by single nucleotide polymorphism (SNP) array analysis to point out chromosome segments linked to EGFR mutations. To do so, we compared genetic profiles between EGFR mutated adenocarcinomas (ADC) and KRAS mutated ADC from 24 women with localized lung cancer. Results: Patterns of alterations were different between EGFR and KRAS mutated tumors and specific chromosomes alterations were linked to the EGFR mutated group. Indeed chromosome regions 14q21.3 (p = 0.027), 7p21.3-p21.2 (p = 0.032), 7p21.3 (p = 0.042) and 7p21.2-7p15.3 (p = 0.043) were found significantly amplified in EGFR mutated tumors. Within those regions 3 genes are of special interest ITGB8, HDAC9 and TWIST1. Moreover, homozygous deletions at CDKN2A and LOH at RB1 were identified in EGFR mutated tumors. We therefore tested the existence of a link between EGFR mutation, CDKN2A homozygous deletion and cyclin amplification in a larger series of tumors. Indeed, in a series of non-small-cell lung carcinoma (n = 98) we showed that homozygous deletions at CDKN2A were linked to EGFR mutations and absence of smoking whereas cyclin amplifications (CCNE1 and CCND1) were associated to TP53 mutations and smoking habit. Conclusion: All together, our results show that genome wide patterns of alteration differ between EGFR and KRAS mutated lung ADC, describe two models of oncogenic cooperation involving either EGFR mutation and CDKN2A deletion or cyclin amplification and TP53 inactivating mutations and identified new chromosome regions at 7p and 14q associated to EGFR mutations in lung cancer.

关键词： TP53 Mutation Homozygous Deletion EGFR Mutation single nucleotide polymorphism array single nucleotide polymorphism Locus

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single nucleotide polymorphisms

Single Nucleotide Polymorphisms

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作者： Nameeta Shah

The particular order of the 4 different bases: adenine (A), thymine (T), cytosine (C), and guanine (G) that are present in DNA, arranged along the sugar-phosphate backbone of DNA is called its sequence; the DNA sequen... 详细信息

关键词： Metagenomics Chronic Granulomatous Disease single nucleotide polymorphism Autism Spectrum Disorder Noonan Syndrome single nucleotide polymorphism array

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Germline polymorphisms as modulators of cancer phenotypes

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BMC MEDICINE 2008年第1期6卷 27-27页

作者： Tan, Patrick Duke NUS Grad Med Sch Singapore 169547 Singapore Genome Inst Singapore Singapore 138672 Singapore

Identifying the complete repertoire of genes and genetic variants that regulate the pathogenesis and progression of human disease is a central goal of post-genomic biomedical research. In cancer, recent studies have shown that genome-wide association studies can be successfully used to identify germline polymorphisms associated with an individual's susceptibility to malignancy. In parallel to these reports, substantial work has also shown that patterns of somatic alterations in human tumors can be successfully employed to predict disease prognosis and treatment response. A paper by Van Ness et al. published this month in BMC Medicine reports the initial results of a multi-institutional consortium for multiple myeloma designed to evaluate the role of germline polymorphisms in influencing multiple myeloma clinical outcome. Applying a custom-designed single nucleotide polymorphism microarray to two separate patient cohorts, the investigators successfully identified specific combinations of germline polymorphisms significantly associated with early clinical relapse. These results raise the exciting possibility that besides somatically acquired alterations, germline genetic background may also exert an important influence on cancer patient prognosis and outcome. Future 'personalized medicine' strategies for cancer may thus require incorporating genomic information from both tumor cells and the non-malignant patient genome.

关键词： Multiple Myeloma single nucleotide polymorphism array Somatic Alteration Germline polymorphism single nucleotide polymorphism Association

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PLASQ: a generalized linear model-based procedure to determine allelic dosage in cancer cells from SNP array data

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BIOSTATISTICS 2007年第2期8卷 323-336页

作者： Laframboise, Thomas Harrington, David Weir, Barbara A. Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA Harvard Univ Sch Publ Hlth Dept Biostat Boston MA 02115 USA

Human cancer is largely driven by the acquisition of mutations. One class of such mutations is copy number polymorphisms, comprised of deviations from the normal diploid two copies of each autosomal chromosome per cell. We describe a probe-level allele-specific quantitation (PLASQ) procedure to determine copy number contributions from each of the parental chromosomes in cancer cells from single-nucleotide polymorphism (SNP) microarray data. Our approach is based upon a generalized linear model that takes advantage of a novel classification of probes on the array. As a result of this classification, we are able to fit the model to the data using an expectation-maximization algorithm designed for the purpose. We demonstrate a strong model fit to data from a variety of cell types. In normal diploid samples, PLASQ is able to genotype with very high accuracy. Moreover, we are able to provide a generalized genotype in cancer samples (e.g. CCCCT at an amplified SNP). Our approach is illustrated on a variety of lung cancer cell lines and tumors, and a number of events are validated by independent computational and experimental means. An R software package containing the methods is freely available.

关键词： allelic imbalance cancer genomics DNA copy number expectation-maximization algorithm generalized linear model single nucleotide polymorphism array

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A procedure for the detection of linkage with high density SNP arrays in a large pedigree with colorectal cancer

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BMC CANCER 2007年第1期7卷 1-8页

作者： Middeldorp, Anneke Jagmohan-Changur, Shantie Helmer, Quinta van der Klift, Heleen M. Tops, Carli M. J. Vasen, Hans F. A. Devilee, Peter Morreau, Hans Houwing-Duistermaat, Jeanine J. Wijnen, Juul T. van Wezel, Tom Leiden Univ Med Ctr Dept Pathol Leiden Netherlands Leiden Univ Med Ctr Dept Human Genet Leiden Netherlands Leiden Univ Med Ctr Dept Med Stat & Bioinformat Leiden Netherlands Leiden Univ Med Ctr Dept Clin Genet Leiden Netherlands Netherlands Fdn Detect Hereditary Tumours Leiden Netherlands

Background: The apparent dominant model of colorectal cancer (CRC) inheritance in several large families, without mutations in known CRC susceptibility genes, suggests the presence of so far unidentified genes with strong or moderate effect on the development of CRC. Linkage analysis could lead to identification of susceptibility genes in such families. In comparison to classical linkage analysis with multi-allelic markers, single nucleotide polymorphism ( SNP) arrays have increased information content and can be processed with higher throughput. Therefore, SNP arrays can be excellent tools for linkage analysis. However, the vast number of SNPs on the SNP arrays, combined with large informative pedigrees ( e. g. > 35 - 40 bits), presents us with a computational complexity that is challenging for existing statistical packages or even exceeds their capacity. We therefore setup a procedure for linkage analysis in large pedigrees and validated the method by genotyping using SNP arrays of a colorectal cancer family with a known MLH1 germ line mutation. Methods: Quality control of the genotype data was performed in Alohomora, Mega2 and SimWalk2, with removal of uninformative SNPs, Mendelian inconsistencies and Mendelian consistent errors, respectively. Linkage disequilibrium was measured by SNPLINK and Merlin. Parametric linkage analysis using two flanking markers was performed using MENDEL. For multipoint parametric linkage analysis and haplotype analysis, SimWalk2 was used. Results: On chromosome 3, in the MLH1-region, a LOD score of 1.9 was found by parametric linkage analysis using two flanking markers. On chromosome 11 a small region with LOD 1.1 was also detected. Upon linkage disequilibrium removal, multipoint linkage analysis yielded a LOD score of 2.1 in the MLH1 region, whereas the LOD score dropped to negative values in the region on chromosome 11. Subsequent haplotype analysis in the MLH1 region perfectly matched the mutation status of the family members. Conc

关键词： Linkage Analysis Lynch Syndrome single nucleotide polymorphism array Large Pedigree Multipoint Linkage Analysis Linkage Analysis Lynch Syndrome single nucleotide polymorphism array Large Pedigree Multipoint Linkage Analysis

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Genome-wide analysis for loss of heterozygosity in primary and recurrent phyllodes tumor and fibroadenoma of breast using single nucleotide polymorphism arrays

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BREAST CANCER RESEARCH AND TREATMENT 2006年第3期97卷 301-309页

作者： Wang, Zhigang Charles Buraimoh, Ayodele Iglehart, James Dirk Richardson, Andrea Lynn Brigham & Womens Hosp Dept Pathol Boston MA 02115 USA Dana Farber Canc Inst Dept Canc Biol Boston MA USA Brigham & Womens Hosp Dept Surg Boston MA 02115 USA

Phyllodes tumors of the breast are biphasic stromal and epithelial tumors histologically similar to benign fibroadenomas, but with a neoplastic stromal component. In contrast to fibroadenoma, phyllodes tumors can recur and be locally aggressive or be malignant. This study uses SNP array analysis to present a genome-wide map of loss of heterozygosity (LOH) in a cohort of phyllodes tumors and fibroadenomas. LOH is frequent and sometimes extensive in phyllodes tumors, but is rarely seen in fibroadenomas. There is heterogeneity between phyllodes tumors of different patients and no one LOH marker identifies a majority of these lesions. However, a subset of LOH loci occur in multiple cases of phyllodes tumors and are not found in fibroadenomas. Primary phyllodes tumors and paired recurrences from the same patient share common regions of LOH. In contrast, metachronous fibroadenomas from the same patient have different LOH patterns with no indication of a shared origin. Specific LOH loci may be associated with pathologic progression in recurrent phyllodes tumors. In a single case of phyllodes tumor containing a malignant epithelial component the malignant epithelium and stroma partially share an LOH genotype, suggesting a common precursor cell for the biphasic malignant components.

关键词： fibroadenoma loss of heterozygosity phyllodes tumor single nucleotide polymorphism array stem or precursor cell

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Advancement in characterization of genomic alterations for improved diagnosis, treatment and prognostics in cancer

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EXPERT REVIEW OF MOLECULAR DIAGNOSTICS 2006年第1期6卷 39-50页

作者： Zhou, XF Yu, TW Cole, SW Wong, DTW Univ Calif Los Angeles Sch Dent Dent Res Inst Los Angeles CA 90024 USA Univ Calif Los Angeles Jonsson Comprehens Canc Ctr Los Angeles CA 90024 USA Univ Calif Los Angeles Div Hematol Oncol Dept Med David Geffen Sch Med Los Angeles CA USA Univ Calif Los Angeles Inst Mol Biol Los Angeles CA USA Univ Calif Los Angeles Div Head & Neck Surg Otolaryngol David Geffen Sch Med Los Angeles CA USA Univ Calif Los Angeles Henry Samueli Sch Engn Los Angeles CA USA

Most human cancers are characterized by genetic instabilities. These instabilities manifest themselves as a series of genetic alterations, including discrete mutations and chromosomal aberrations. With the human genome deciphered, high-throughput technologies are rapidly advancing the field to generate genome-wide gene expression and mutation profiles that are highly correlative of biologic and disease phenotypes. While recent advancement in comprehensive genomic characterization presents an unprecedented opportunity for advancing the treatment of cancer, there are still many challenges that need to be overcome before we can fully utilize genomic markers and targets for cancer prediction, diagnostics, treatment and prognostics. This review describes recent advances in comprehensive genomic characterization at the DNA level, and considers some of the challenges that remain for defining the precise genomic portrait of tumors. Potential solutions that may help overcome these challenges are also offered.

关键词： comparative genomic hybridization loss of heterozygosity multicolor fluorescence in situ hybridization personalized therapies single nucleotide polymorphism array spectral karyotyping tiling array

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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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Genome-wide loss of heterozygosity and copy number alteration in esophageal squamous cell carcinoma using the Affymetrix GeneChip Mapping 10 K array

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BMC GENOMICS 2006年第1期7卷 299-299页

作者： Hu, Nan Wang, Chaoyu Hu, Ying Yang, Howard H. Kong, Li-Hui Lu, Ning Su, Hua Wang, Quan-Hong Goldstein, Alisa M. Buetow, Kenneth H. Emmert-Buck, Michael R. Taylor, Philip R. Lee, Maxwell P. NCI Genet Epidemiol Branch Div Canc Epidemiol & Genet Bethesda MD 20892 USA NCI Lab Populat Genet Ctr Canc Res Bethesda MD 20892 USA Shanxi Canc Hosp Taiyuan 030013 Shanxi Peoples R China Chinese Acad Med Sci Canc Inst & Hosp Beijing 100021 Peoples R China NCI Pathol Lab Ctr Canc Res Bethesda MD 20892 USA

Background: Esophageal squamous cell carcinoma (ESCC) is a common malignancy worldwide. Comprehensive genomic characterization of ESCC will further our understanding of the carcinogenesis process in this disease. Results: Genome-wide detection of chromosomal changes was performed using the Affymetrix GeneChip 10 K single nucleotide polymorphism (SNP) array, including loss of heterozygosity (LOH) and copy number alterations (CNA), for 26 pairs of matched germ-line and micro-dissected tumor DNA samples. LOH regions were identified by two methods -using Affymetrix's genotype call software and using Affymetrix's copy number alteration tool (CNAT) software -and both approaches yielded similar results. Non-random LOH regions were found on 10 chromosomal arms (in decreasing order of frequency: 17p, 9p, 9q, 13q, 17q, 4q, 4p, 3p, 15q, and 5q), including 20 novel LOH regions (10 kb to 4.26 Mb). Fifteen CNA-loss regions (200 kb to 4.3 Mb) and 36 CNA-gain regions (200 kb to 9.3 Mb) were also identified. Conclusion: These studies demonstrate that the Affymetrix 10 K SNP chip is a valid platform to integrate analyses of LOH and CNA. The comprehensive knowledge gained from this analysis will enable improved strategies to prevent, diagnose, and treat ESCC.

关键词： Esophageal Squamous Cell Carcinoma Esophageal Squamous Cell Carcinoma Patient single nucleotide polymorphism array Deletion Region Copy Number Alteration

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A molecular scheme for improved characterization of human embryonic stem cell lines

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BMC BIOLOGY 2006年第1期4卷 28-28页

作者： Josephson, Richard Sykes, Gregory Liu, Ying Ording, Carol Xu, Weining Zeng, Xianmin Shin, Soojung Loring, Jeanne Maitra, Anirban Rao, Mahendra S. Auerbach, Jonathan M. ATCC Stem Cell Ctr Manassas VA USA ATCC Dept Cell Biol Manassas VA USA NIA Neurosci Lab NIH Baltimore MD 21224 USA Buck Inst Age Res Novato CA USA Burnham Inst La Jolla CA 92037 USA Johns Hopkins Univ Sch Med Dept Pathol Baltimore MD 21218 USA Johns Hopkins Univ Sch Med Dept Oncol Baltimore MD 21218 USA Johns Hopkins Univ Sch Med Dept Genet Med Baltimore MD 21218 USA Invitrogen Corp Carlsbad CA USA

Background: Human embryonic stem cells (hESC) offer a renewable source of a wide range of cell types for use in research and cell-based therapies to treat disease. Inspection of protein markers provides important information about the current state of the cells and data for subsequent manipulations. However, hESC must be routinely analyzed at the genomic level to guard against deleterious changes during extensive propagation, expansion, and manipulation in vitro. Results: We found that short tandem repeat (STR) analysis, human leukocyte antigen (HLA) typing, single nucleotide polymorphism (SNP) genomic analysis, mitochondrial DNA sequencing, and gene expression analysis by microarray can be used to fully describe any hESC culture in terms of its identity, stability, and undifferentiated state. Conclusion: Here we describe, using molecular biology alone, a comprehensive characterization of 17 different hESC lines. The use of amplified nucleic acids means that for the first time full characterization of hESC lines can be performed with little time investment and a minimum of material. The information thus gained will facilitate comparison of lines and replication of results between laboratories.

关键词： Human Leukocyte Antigen Short Tandem Repeat Undifferentiated State single nucleotide polymorphism array hESC Line

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