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Bivariate segmentation of SNP-array data for allele-specific copy number analysis in tumour samples

BMC BIOINFORMATICS 2013年第1期14卷 1-10页

作者： Mosen-Ansorena, David Maria Aransay, Ana CIC bioGUNE & CIBERehd Genome Anal Platform Derio 48160 Spain

Background: SNP arrays output two signals that reflect the total genomic copy number (LRR) and the allelic ratio (BAF), which in combination allow the characterisation of allele-specific copy numbers (ASCNs). While methods based on hidden Markov models (HMMs) have been extended from array comparative genomic hybridisation (aCGH) to jointly handle the two signals, only one method based on change-point detection, ASCAT, performs bivariate segmentation. Results: In the present work, we introduce a generic framework for bivariate segmentation of SNP array data for ASCN analysis. For the matter, we discuss the characteristics of the typically applied BAF transformation and how they affect segmentation, introduce concepts of multivariate time series analysis that are of concern in this field and discuss the appropriate formulation of the problem. The framework is implemented in a method named CnaStruct, the bivariate form of the structural change model (SCM), which has been successfully applied to transcriptome mapping and aCGH. Conclusions: On a comprehensive synthetic dataset, we show that CnaStruct outperforms the segmentation of existing ASCN analysis methods. Furthermore, CnaStruct can be integrated into the workflows of several ASCN analysis tools in order to improve their performance, specially on tumour samples highly contaminated by normal cells.

关键词： single nucleotide polymorphism array Allelic Ratio Bivariate Case Affymetrix Platform Minkowski Distance

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Cytogenetic, fluorescence in situ hybridization, and genomic array characterization of chronic myeloid leukemia with cryptic BCR-ABL1 fusions

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CANCER GENETICS 2015年第7-8期208卷 396-403页

作者： Shao, Lina Miller, Sue Keller-Ramey, Jennifer Zhang, Yang Roulston, Diane Univ Michigan Dept Pathol Clin Cytogenet Lab Ann Arbor MI 48109 USA

Chronic myeloid leukemia (CML) is characterized by the breakpoint cluster region (BCR)-Abelson murine leukemia (ABL1) fusion gene. In approximately 1% of CML cases, the Philadelphia chromosome associated with the BCR-ABL1 fusion gene is not present, and the BCR-ABL1 fusion gene is generated by cryptic insertion or sequential translocations. In this study, we describe the cytogenetic and molecular features of five CML patients with cryptic BCR-ABL1 fusion genes using karyotype, fluorescence in situ hybridization (FISH), and whole genome single nucleotide polymorphism array techniques. Two cases of CML in the chronic phase (CP) had a normal karyotype, and three cases of CML in the blast phase (BP) had an abnormal karyotype with neither a typical nor variant t(9;22). By BCR-ABL1 metaphase FISH analysis, we found that fusion signals were localized on chromosomes 9 (3 cases), 22 (1 case), and both 9 and 22 (1 case). In two cases of CML-BP, duplication of the BCR-ABL1 fusion gene occurred as a result of mitotic recombination between homologous chromosomes. Copy number losses involving the IKZF1 gene were observed in two patients with CML-BP. This study demonstrates for the first time the acquisition of additional BCR-ABL1 fusion genes through mitotic recombination in CML with cryptic BCR-ABL1.

关键词： Chronic myeloid leukemia cryptic BCR-ABL1 single nucleotide polymorphism array

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SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling

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JOURNAL OF MOLECULAR MEDICINE-JMM 2013年第3期91卷 381-393页

作者： Dasgupta, Santanu Jang, Jin Sung Shao, Chunbo Mukhopadhyay, Nitai D. Sokhi, Upneet K. Das, Swadesh K. Brait, Mariana Talbot, Conover Yung, Rex C. Begum, Shahnaz Westra, William H. Hoque, Mohammad Obaidul Yang, Ping Yi, Joanne E. Lam, Stephan Gazdar, Adi F. Fisher, Paul B. Jen, Jin Sidransky, David Virginia Commonwealth Univ VCU Inst Mol Med VCU Massey Canc Ctr Dept Human & Mol GenetSch Med Richmond VA 23220 USA Mayo Clin Div Pulm & Crit Care Med Dept Med Rochester MN USA Johns Hopkins Univ Dept Otolaryngol Head & Neck Surg Baltimore MD USA Virginia Commonwealth Univ Dept Biostat Richmond VA USA Johns Hopkins Univ Inst Basic Biomed Sci Baltimore MD USA Johns Hopkins Univ Dept Pulm & Crit Care Med Baltimore MD USA Mayo Clin Dept Hlth Sci Res Rochester MN USA Mayo Clin Dept Lab Med & Pathol Rochester MN USA British Columbia Canc Res Ctr Dept Integrat Oncol Vancouver BC V5Z 1L3 Canada Univ Texas SW Med Ctr Dallas Hamon Ctr Therapeut Oncol Res Dallas TX 75390 USA

The purpose of this study was to identify key genetic pathways involved in non-small cell lung cancer (NSCLC) and understand their role in tumor progression. We performed a genome wide scanning using paired tumors and corresponding 16 mucosal biopsies from four follow-up lung cancer patients on Affymetrix 250K-NSpI array platform. We found that a single gene SH3GL2 located on human chromosome 9p22 was most frequently deleted in all the tumors and corresponding mucosal biopsies. We further validated the alteration pattern of SH3GL2 in a substantial number of primary NSCLC tumors at DNA and protein level. We also overexpressed wild-type SH3GL2 in three NSCLC cell lines to understand its role in NSCLC progression. Validation in 116 primary NSCLC tumors confirmed frequent loss of heterozygosity of SH3GL2 in overall 51 % (49/97) of the informative cases. We found significantly low (p = 0.0015) SH3GL2 protein expression in 71 % (43/60) primary tumors. Forced overexpression of wild-type (wt) SH3GL2 in three NSCLC cell lines resulted in a marked reduction of active epidermal growth factor receptor (EGFR) expression and an increase in EGFR internalization and degradation. Significantly decreased in vitro (p = 0.0015-0.030) and in vivo (p = 0.016) cellular growth, invasion (p = 0.029-0.049), and colony formation (p = 0.023-0.039) were also evident in the wt-SH3GL2-transfected cells accompanied by markedly low expression of activated AKT(Ser(473)), STAT3 (Tyr(705)), and PI3K. Downregulation of SH3GL2 interactor USP9X and activated -catenin was also evident in the SH3GL2-transfected cells. Our results indicate that SH3GL2 is frequently deleted in NSCLC and regulates cellular growth and invasion by modulating EGFR function.

关键词： single nucleotide polymorphism array Lung cancer SH3GL2 Deletion

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Digital karyotyping technology: exploring the cancer genorne

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EXPERT REVIEW OF MOLECULAR DIAGNOSTICS 2005年第6期5卷 917-925页

作者： Parrett, TJ Yan, H Duke Univ Med Ctr Dept Pathol Brain Tumor Ctr Durham NC 27710 USA

Identifying gene-specific alterations in cancer genomes has revealed molecules that are causal effectors of carcinogenesis and specific targets for cancer molecular diagnosis and molecular-based cancer therapies. Whole-genome analyses of many cancer genomes at the resolution of single genes Is thus a desirable yet incompletely realized goal that could expedite progress in cancer diagnosis and treatment. Although methods for routine whole-genome sequencing or high-resolution epigenetic measurements are currently under development, high-resolution measurements of gone copy number, or 'gone dosage', are now underway in several laboratories. Digital karyotyping, array comparative genomic hybridization, and single nucleotide polymorphism arrays are techniques that have the potential to detect gone amplification, homozygous deletion and loss of heterozygosity at or below the average length of single genes. Recently, digital karyotyping of a small number (< 20) of colon and brain cancer genomes;has revealed tumor cases with significant genetic dosage alterations affecting few and, in some cases, only one complete gene. These experiments suggest that gene-specific gene dosage alterations may be sufficiently frequent to enable the identification of promising tumor gene candidates in small-scale experiments. The purpose of this review is to describe our understanding of cancer as a genetic disease, review the basic principles, methodologies and interpretational issues of traditional and high-resolution whole-genome screens, and describe the potential of our first detailed look at whole cancer genomes;for progress in the understanding and treatment of cancer.

关键词： array comparative genomic hybridization cancer genome digital karyotyping gene dosage microarray analysis representational oligonucleotide single nucleotide polymorphism array whole-genome analysis

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Comparative clinical genetic testing in spontaneous miscarriage: Insights from a study in Southern Chinese women

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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE 2021年第12期25卷 5721-5728页

作者： Cai, Meiying Lin, Na Xu, Liangpu Huang, Hailong Fujian Med Univ Dept Prenatal Diag Ctr Fujian Matern & Child Hlth Hosp Fujian Key Lab Prenatal Diag & Birth DefectAffil Fuzhou Peoples R China

single nucleotide polymorphism (SNP) array and karyotype analyses were conducted on 441 spontaneous miscarriage placental villous tissues collected from women from southern China. Subsequently, the results from these two analyses were compared to evaluate the best diagnostic strategy for subsequent pre-pregnancy planning. Here, the success rate of genetic testing using karyotyping and SNP array analysis was 78.46% (346/441) and 100.0% (441/441), respectively. The abnormality rate estimated by both methods was 54.9% (242/441). Three hundred and forty-six cases were successfully detected via both SNP array and karyotype analyses;the rate of consistent detection was 96.24% (333/346), whereas 13 cases were not consistent. There was no substantial positive correlation between age and genetic abnormalities such as Turner syndrome, structural variation or euploidy state in the different age groups studied. However, the aneuploidy rate was significantly different in each age group. Thus, although SNP array has higher success rate and resolution in genetic abnormality detection, supplementary karyotype analysis is needed for a more accurate revelation of the genetic aetiology of miscarriages. Therefore, this study indicates that simultaneous karyotype and SNP array analyses should be performed for spontaneous miscarriages. Furthermore, miscarriages irrespective of maternal age must be genetically analysed.

关键词： genetic abnormalities single nucleotide polymorphism array spontaneous miscarriages

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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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Patients with polyclonal hepatocellular carcinoma are at a high risk of early recurrence and have a poor recurrence-free survival period

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HEPATOLOGY INTERNATIONAL 2022年第1期16卷 135-147页

作者： Kaibori, Masaki Sakai, Kazuko Matsushima, Hideyuki Kosaka, Hisashi Matsui, Kosuke De Velasco, Marco A. Sekimoto, Mitsugu Nishio, Kazuto Kansai Med Univ Hirakata Hosp Dept Surg Hirakata Osaka Japan Kindai Univ Fac Med Dept Genome Biol 377-2 Ohno Higashi Osakasayama Osaka 5898511 Japan

Background/purpose of the study Tumor heterogeneity based on copy number variations is associated with the evolution of cancer and its clinical grade. Clonal composition (CC) represents the number of clones based on the distribution of B-allele frequency (BAF) obtained from a genome-wide single nucleotide polymorphism (SNP) array. A higher CC number represents a high degree of heterogeneity. We hypothesized and evaluated that the CC number in hepatocellular carcinoma (HCC) tissues might be associated with the clinical outcomes of patients. Methods Somatic mutation, whole transcriptome, and CC number based on copy number variations of 36 frozen tissue samples of operably resected HCC tissues were analyzed by targeted deep sequencing, transcriptome analysis, and SNP array. Results The samples were classified into the heterogeneous tumors as poly-CC (n = 26) and the homogeneous tumors as mono-CC (n = 8). The patients with poly-CC had a higher rate of early recurrence and a significantly shorter recurrence-free survival period than the mono-CC patients (7.0 months vs. not reached, p = 0.0084). No differences in pathogenic non-synonymous mutations, such as TP53, were observed between the two groups when targeted deep sequencing was applied. A transcriptome analysis showed that cell cycle-related pathways were enriched in the poly-CC tumors, compared to the mono-CC tumors. Poly-CC HCC is highly proliferative and has a high risk of early recurrence. Conclusion CC is a possible candidate biomarker for predicting the risk of early postoperative recurrence and warrants further investigation.

关键词： Clonal composition Hepatocellular carcinoma Recurrence-free survival Copy number variation Gene expression Gene set enrichment analysis Early recurrence single nucleotide polymorphism array B-allele frequency Proliferation

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Large-scale data integration framework provides a comprehensive view on glioblastoma multiforme

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GENOME MEDICINE 2010年第9期2卷 1-12页

作者： Ovaska, Kristian Laakso, Marko Haapa-Paananen, Saija Louhimo, Riku Chen, Ping Aittomaki, Viljami Valo, Erkka Nunez-Fontarnau, Javier Rantanen, Ville Karinen, Sirkku Nousiainen, Kari Lahesmaa-Korpinen, Anna-Maria Miettinen, Minna Saarinen, Lilli Kohonen, Pekka Wu, Jianmin Westermarck, Jukka Hautaniemi, Sampsa Univ Helsinki Inst Biomed Computat Syst Biol Lab FIN-00014 Helsinki Finland Univ Helsinki Genome Scale Biol Res Program FIN-00014 Helsinki Finland VTT Tech Res Ctr FI-20521 Turku Finland Univ Turku FI-20521 Turku Finland Univ Turku Turku Ctr Biotechnol FI-20520 Turku Finland Abo Akad Univ FI-20520 Turku Finland Univ Turku Dept Pathol FI-20521 Turku Finland Turku Univ Hosp FI-20521 Turku Finland

Background: Coordinated efforts to collect large-scale data sets provide a basis for systems level understanding of complex diseases. In order to translate these fragmented and heterogeneous data sets into knowledge and medical benefits, advanced computational methods for data analysis, integration and visualization are needed. Methods: We introduce a novel data integration framework, Anduril, for translating fragmented large-scale data into testable predictions. The Anduril framework allows rapid integration of heterogeneous data with state-of-the-art computational methods and existing knowledge in bio-databases. Anduril automatically generates thorough summary reports and a website that shows the most relevant features of each gene at a glance, allows sorting of data based on different parameters, and provides direct links to more detailed data on genes, transcripts or genomic regions. Anduril is open-source;all methods and documentation are freely available. Results: We have integrated multidimensional molecular and clinical data from 338 subjects having glioblastoma multiforme, one of the deadliest and most poorly understood cancers, using Anduril. The central objective of our approach is to identify genetic loci and genes that have significant survival effect. Our results suggest several novel genetic alterations linked to glioblastoma multiforme progression and, more specifically, reveal Moesin as a novel glioblastoma multiforme-associated gene that has a strong survival effect and whose depletion in vitro significantly inhibited cell proliferation. All analysis results are available as a comprehensive website. Conclusions: Our results demonstrate that integrated analysis and visualization of multidimensional and heterogeneous data by Anduril enables drawing conclusions on functional consequences of large-scale molecular data. Many of the identified genetic loci and genes having significant survival effect have not been reported earlier in the context of gliob

关键词： Glioblastoma Multiforme single nucleotide polymorphism array Exon array Exon array Data Gene Expression Platform

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High resolution genomic profiling and classical cytogenetics in a group of benign and atypical meningiomas

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CANCER GENETICS 2011年第10期204卷 541-549页

作者： Holland, Heidrun Mocker, Kristin Ahnert, Peter Kirsten, Holger Hantmann, Helene Koschny, Ronald Bauer, Manfred Schober, Ralf Scholz, Markus Meixensberger, Juergen Krupp, Wolfgang Univ Leipzig Dept Neurosurg Leipzig Germany Univ Leipzig Translat Ctr Regenerat Med TRM Leipzig Germany Univ Leipzig Inst Med Informat Stat & Epidemiol Leipzig Germany Heidelberg Univ Dept Internal Med D-6900 Heidelberg Germany Univ Leipzig Div Neuropathol Leipzig Germany Fraunhofer Inst Cell Therapy & Immunol Leipzig Germany Univ Leipzig LIFE Ctr Leipzig Interdisciplinary Res Cluster Ge Leipzig Germany

Meningiomas are classified as benign, atypical, or anaplastic. The majority are sporadic, solitary, and benign tumors with favorable prognoses. However, the prognosis for patients with anaplastic meningiomas remains less favorable. High resolution genomic profiling has the capacity to provide more detailed information. Therefore, we analyzed genomic aberrations of benign and atypical meningiomas using single nucleotide polymorphism (SNP) array, combined with G-banding by trypsin using Giemsa stain (GTG banding), spectral karyotyping, and locus-specific fluorescence in situ hybridization (FISH). We confirmed frequently detected chromosomal aberrations in meningiomas and identified novel genetic events. Applying SNP array, we identified constitutional de novo loss or gain within chromosome 22 in three patients, possibly representing inherited causal events for meningioma formation. We show evidence for somatic segmental uniparental disomy in regions 4p16.1, 7q31.2, 8p23.2, and 9p22.1 not previously described for primary meningioma. GTG-banding and spectral karyotyping detected a novel balanced reciprocal translocation t(4;10)(q12;q26) in one benign meningioma. A paracentric inversion within 1p36, previously described as novel, was detected as a recurrent chromosomal aberration in benign and atypical meningiomas. Analyses of tumors and matched normal tissues with a combination of SNP arrays and complementary techniques will help to further elucidate potentially causal genetic events for tumorigenesis of meningioma.

关键词： Meningioma cytogenetics single nucleotide polymorphism array segmental uniparental disomies paracentric inversion

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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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