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Genomic Imbalances (genomic + imbalance)
Selected AbstractsDetection of pathogenic gene copy number variations in patients with mental retardation by genomewide oligonucleotide array comparative genomic hybridization,,HUMAN MUTATION, Issue 11 2007Yao-Shan Fan Abstract Genomic imbalance is a major cause of developmental disorders. Microarray-based comparative genomic hybridization (aCGH) has revealed frequent imbalances associated with clinical syndromes, but also a large number of copy number variations (CNVs), which have complicated the interpretation of results. We studied 100 consecutive patients with unexplained mental retardation and a normal karyotype using several platforms of CGH arrays. A genomewide array with 44,290 oligonucleotide probes (OaCGH44K) detected imbalances in 15% of cases studied with sizes ranged from 459,kb to 19,Mb while revealing a small number of CNVs (0.72/individual). Another platform with ,240,000 oligonucleotide probes (OaCGH244K) revealed a large number of CNVs (20/individual) in selected cases and their normal parents. We used a comprehensive approach for interpreting the results of aCGH, including consideration of the size, inheritance and gene content of CNVs, and consultation with an online Database of Genomic Variants (DGV) and Online Mendelian Inheritance in Men (OMIM) for information on the genes involved. Our study suggests that genomewide oligonucleotide arrays such as the OaCGH44K platform can be used as a powerful diagnostic tool for detection of genomic imbalances associated with unexplained mental retardation or syndromic autism spectrum disorders. It is interesting to note that a small number of common variants were revealed by OaCGH244K in some study subjects but not in their parents and that some inherited CNVs had altered breakpoints. Further investigations on these alterations may provide useful information for understanding the mechanism of CNVs. Hum Mutat 28(11),1124,1132, 2007. © 2007 Wiley-Liss, Inc. [source] Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes frequently altered in primary tumors: An approach to identify candidate genes involved in tumor developmentGENES, CHROMOSOMES AND CANCER, Issue 6 2009Edoardo Missiaglia Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. They resemble developing skeletal muscle and are histologically divided into two main subtypes; alveolar and embryonal RMS. Characteristic genomic aberrations, including the PAX3 - and PAX7-FOXO1 fusion genes in alveolar cases, have led to increased understanding of their molecular biology. Here, we determined the effect of genomic copy number on gene expression levels through array comparative genomic hybridization (CGH) analysis of 13 RMS cell lines, confirmed by multiplex ligation-dependent probe amplification copy number analyses, combined with their corresponding expression profiles. Genes altered at the transcriptional level by genomic imbalances were identified and the effect on expression was proportional to the level of genomic imbalance. Extrapolating to a public expression profiling dataset for 132 primary RMS identified features common to the cell lines and primary samples and associations with subtypes and fusion gene status. Genes identified such as CDK4 and MYCN are known to be amplified, overexpressed, and involved in RMS tumorigenesis. Of the many genes identified, those with likely functional relevance included CENPF, DTL, MYC, EYA2, and FGFR1. Copy number and expression of FGFR1 was validated in additional primary material and found amplified in 6 out of 196 cases and overexpressed relative to skeletal muscle and myoblasts, with significantly higher expression levels in the embryonal compared with alveolar subtypes. This illustrates the ability to identify genes of potential significance in tumor development through combining genomic and transcriptomic profiles from representative cell lines with publicly available expression profiling data from primary tumors. © 2009 Wiley-Liss, Inc. [source] Genomic imbalances in CML blast crisis: 8q24.12,q24.13 Segment identified as a common region of over-representationGENES, CHROMOSOMES AND CANCER, Issue 4 2003Susan M. Gribble The acute phase of chronic myeloid leukemia (CML) is accompanied by secondary chromosomal changes. The additional changes have a non-random pattern; however, highly abnormal (marker) chromosomes are reported in some 20% of abnormal karyotypes. These marker chromosomes have proved to be beyond the resolution of conventional G-banding analysis. We used molecular cytogenetic techniques to determine the structure of complex chromosome markers in 10 CML-derived cell lines after our investigations of CML patients in blast crisis. Multicolor fluorescence in situ hybridization identified a multitude of structural chromosome aberrations. In addition, genomic gains identified by comparative genomic hybridization (CGH) were mapped to highly complex marker chromosomes in more than one cell line. The most common genomic loss detected by CGH affected chromosome 9, whereas the most common genomic gains affected, in order of frequency, the sequences of 8q, 6, and 13q. The smallest discrete amplification on 8q was identified in cell line MEG-01. This amplicon contains sequences represented by the marker D8S263/RMC08P029 but did not contain the proximal MYC gene or a more distal marker, D8S256/RMC08P025. We determined the size of the amplicon to be less than the chromosome segment 8q24.12,q24.13. The use of region- and locus-specific probes to analyze the organization of highly complex marker structures aided the identification of preferentially amplified genomic regions. The resultant amplifications could harbor gene(s) driving disease progression. © 2003 Wiley-Liss, Inc. [source] Genetic imbalances revealed by comparative genomic hybridization in osteosarcomasINTERNATIONAL JOURNAL OF CANCER, Issue 4 2002Toshifumi Ozaki Abstract Osteosarcomas are the most frequent bone sarcomas. The molecular chromosomal aberrations in osteosarcomas were analyzed by comparative genomic hybridization (CGH). We studied 47 frozen tumors (41 primary samples, 6 relapses) in osteosarcoma patients registered in the Cooperative Osteosarcoma Study (COSS) protocol. Genomic imbalances were detected in 40 of 41 primary tumors and 6 of 6 relapsed tumors. Gains were more frequent than losses (ratio of 1.3:1). The median number of changes was 16 and 12 in primary and relapsed osteosarcomas, respectively. The median number of aberrations in primary high-grade osteosarcomas (17.0) was significantly higher than in low- or intermediate-grade osteosarcoma subtypes (3.0) (p = 0.038). The most frequent gains included 8q, 1p21-p31 and 1q21-q24, and the most frequent losses were 10q, 5q and 13q. High-level gains were observed on 8q23-q24, 17p13 and 1q21-q24. A gain of 19p (p < 0.001) or loss of 9p (p = 0.027) was more frequent in poor responders than in good responders. Univariate analysis revealed that patients with primary metastases (p = 0.002), poor histologic responses (p = 0.005), high-level gains of 19p (p = 0.012) or losses of 13q14 (p = 0.042) had significantly lower event-free survival (EFS), whereas patients with a loss of 5q (p = 0.007) or a loss of 10q21-22 (p = 0.017) had significantly higher EFS than patients without these aberrations. Multivariate analysis demonstrated that primary metastasis, loss of 13q14 and loss of 5q were independent prognostic factors. The findings of our study seem to be useful for evaluating the prognosis of patients and may finally lead to treatment strategies based on genetic background of osteosarcoma. © 2002 Wiley-Liss, Inc. [source] Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes frequently altered in primary tumors: An approach to identify candidate genes involved in tumor developmentGENES, CHROMOSOMES AND CANCER, Issue 6 2009Edoardo Missiaglia Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. They resemble developing skeletal muscle and are histologically divided into two main subtypes; alveolar and embryonal RMS. Characteristic genomic aberrations, including the PAX3 - and PAX7-FOXO1 fusion genes in alveolar cases, have led to increased understanding of their molecular biology. Here, we determined the effect of genomic copy number on gene expression levels through array comparative genomic hybridization (CGH) analysis of 13 RMS cell lines, confirmed by multiplex ligation-dependent probe amplification copy number analyses, combined with their corresponding expression profiles. Genes altered at the transcriptional level by genomic imbalances were identified and the effect on expression was proportional to the level of genomic imbalance. Extrapolating to a public expression profiling dataset for 132 primary RMS identified features common to the cell lines and primary samples and associations with subtypes and fusion gene status. Genes identified such as CDK4 and MYCN are known to be amplified, overexpressed, and involved in RMS tumorigenesis. Of the many genes identified, those with likely functional relevance included CENPF, DTL, MYC, EYA2, and FGFR1. Copy number and expression of FGFR1 was validated in additional primary material and found amplified in 6 out of 196 cases and overexpressed relative to skeletal muscle and myoblasts, with significantly higher expression levels in the embryonal compared with alveolar subtypes. This illustrates the ability to identify genes of potential significance in tumor development through combining genomic and transcriptomic profiles from representative cell lines with publicly available expression profiling data from primary tumors. © 2009 Wiley-Liss, Inc. [source] Homage to Theodor Boveri (1862,1915): Boveri's theory of cancer as a disease of the chromosomes, and the landscape of genomic imbalances in human carcinomas,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 8 2009Thomas Ried First page of article [source] Definitive molecular cytogenetic characterization of 15 colorectal cancer cell lines,GENES, CHROMOSOMES AND CANCER, Issue 3 2010Turid Knutsen In defining the genetic profiles in cancer, cytogenetically aberrant cell lines derived from primary tumors are important tools for the study of carcinogenesis. Here, we present the results of a comprehensive investigation of 15 established colorectal cancer cell lines using spectral karyotyping (SKY), fluorescence in situ hybridization, and comparative genomic hybridization (CGH). Detailed karyotypic analysis by SKY on five of the lines (P53HCT116, T84, NCI-H508, NCI-H716, and SK-CO-1) is described here for the first time. The five lines with karyotypes in the diploid range and that are characterized by defects in DNA mismatch repair had a mean of 4.8 chromosomal abnormalities per line, whereas the 10 aneuploid lines exhibited complex karyotypes and a mean of 30 chromosomal abnormalities. Of the 150 clonal translocations, only eight were balanced and none were recurrent among the lines. We also reviewed the karyotypes of 345 cases of adenocarcinoma of the large intestine listed in the Mitelman Database of Chromosome Aberrations in Cancer. The types of abnormalities observed in the cell lines reflected those seen in primary tumors: there were no recurrent translocations in either tumors or cell lines; isochromosomes were the most common recurrent abnormalities; and breakpoints occurred most frequently at the centromeric/pericentromeric and telomere regions. Of the genomic imbalances detected by array CGH, 87% correlated with chromosome aberrations observed in the SKY studies. The fact that chromosome abnormalities predominantly result in copy number changes rather than specific chromosome or gene fusions suggests that this may be the major mechanism leading to carcinogenesis in colorectal cancer. Published 2009 Wiley-Liss, Inc. [source] Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes frequently altered in primary tumors: An approach to identify candidate genes involved in tumor developmentGENES, CHROMOSOMES AND CANCER, Issue 6 2009Edoardo Missiaglia Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. They resemble developing skeletal muscle and are histologically divided into two main subtypes; alveolar and embryonal RMS. Characteristic genomic aberrations, including the PAX3 - and PAX7-FOXO1 fusion genes in alveolar cases, have led to increased understanding of their molecular biology. Here, we determined the effect of genomic copy number on gene expression levels through array comparative genomic hybridization (CGH) analysis of 13 RMS cell lines, confirmed by multiplex ligation-dependent probe amplification copy number analyses, combined with their corresponding expression profiles. Genes altered at the transcriptional level by genomic imbalances were identified and the effect on expression was proportional to the level of genomic imbalance. Extrapolating to a public expression profiling dataset for 132 primary RMS identified features common to the cell lines and primary samples and associations with subtypes and fusion gene status. Genes identified such as CDK4 and MYCN are known to be amplified, overexpressed, and involved in RMS tumorigenesis. Of the many genes identified, those with likely functional relevance included CENPF, DTL, MYC, EYA2, and FGFR1. Copy number and expression of FGFR1 was validated in additional primary material and found amplified in 6 out of 196 cases and overexpressed relative to skeletal muscle and myoblasts, with significantly higher expression levels in the embryonal compared with alveolar subtypes. This illustrates the ability to identify genes of potential significance in tumor development through combining genomic and transcriptomic profiles from representative cell lines with publicly available expression profiling data from primary tumors. © 2009 Wiley-Liss, Inc. [source] Stage-specific alterations of the genome, transcriptome, and proteome during colorectal carcinogenesis,GENES, CHROMOSOMES AND CANCER, Issue 1 2007Jens K. Habermann To identify sequential alterations of the genome, transcriptome, and proteome during colorectal cancer progression, we have analyzed tissue samples from 36 patients, including the complete mucosa-adenoma-carcinoma sequence from 8 patients. Comparative genomic hybridization (CGH) revealed patterns of stage specific, recurrent genomic imbalances. Gene expression analysis on 9K cDNA arrays identified 58 genes differentially expressed between normal mucosa and adenoma, 116 genes between adenoma and carcinoma, and 158 genes between primary carcinoma and liver metastasis (P < 0.001). Parallel analysis of our samples by CGH and expression profiling revealed a direct correlation of chromosomal copy number changes with chromosome-specific average gene expression levels. Protein expression was analyzed by two-dimensional gel electrophoresis and subsequent mass spectrometry. Although there was no direct match of differentially expressed proteins and genes, the majority of them belonged to identical pathways or networks. In conclusion, increasing genomic instability and a recurrent pattern of chromosomal imbalances as well as specific gene and protein expression changes correlate with distinct stages of colorectal cancer progression. Chromosomal aneuploidies directly affect average resident gene expression levels, thereby contributing to a massive deregulation of the cellular transcriptome. The identification of novel genes and proteins might deliver molecular targets for diagnostic and therapeutic interventions. © Wiley-Liss, Inc. [source] Quantitative microsatellite analysis to delineate the commonly deleted region 1p22.3 in mantle cell lymphomasGENES, CHROMOSOMES AND CANCER, Issue 10 2006Asha Balakrishnan The molecular pathogenesis of mantle cell lymphomas (MCL), a subset of B-cell non-Hodgkin's lymphomas with a poor prognosis, is still poorly understood. In addition to the characteristic primary genetic alteration t(11;14)(q13;q32), several further genetic changes are present in most cases. One of the most frequent genomic imbalances is the deletion of 1p22.1,p31.1 observed in nearly one-third of MCL cases. This might indicate the presence of tumor suppressor gene(s) in this critical region of deletion. Quantitative microsatellite analysis (QuMA) is a real-time PCR-based method to detect DNA copy number changes. Since QuMA has the resolving power to detect subtle genomic alterations, including homozygous deletions, this may help to identify candidate tumor suppressor genes from deleted regions. To gain more insight into the molecular pathogenesis of MCL, QuMA was performed on genomic DNA from 57 MCL cases. Eight microsatellite loci mapping to the chromosomal region 1p22.3 were analyzed. Losses were observed in 51 of the 57 (,89.5%) samples. Two cases showed a homozygous deletion at the locus containing the gene SH3GLB1, which plays a key role in Bax-mediated apoptosis. Two hotspots with copy number losses were detected at chromosomal localizations 85.4 and 86.6 Mb encompassing BCL10 and CLCA2. Both the genes seem to be attractive candidates to study tumor suppressor function in MCL. This article contains Supplementary material available at http://www.interscience.wiley.com/jpages/1045,2257/suppmat. © 2006 Wiley-Liss, Inc. [source] Detection of pathogenic gene copy number variations in patients with mental retardation by genomewide oligonucleotide array comparative genomic hybridization,,HUMAN MUTATION, Issue 11 2007Yao-Shan Fan Abstract Genomic imbalance is a major cause of developmental disorders. Microarray-based comparative genomic hybridization (aCGH) has revealed frequent imbalances associated with clinical syndromes, but also a large number of copy number variations (CNVs), which have complicated the interpretation of results. We studied 100 consecutive patients with unexplained mental retardation and a normal karyotype using several platforms of CGH arrays. A genomewide array with 44,290 oligonucleotide probes (OaCGH44K) detected imbalances in 15% of cases studied with sizes ranged from 459,kb to 19,Mb while revealing a small number of CNVs (0.72/individual). Another platform with ,240,000 oligonucleotide probes (OaCGH244K) revealed a large number of CNVs (20/individual) in selected cases and their normal parents. We used a comprehensive approach for interpreting the results of aCGH, including consideration of the size, inheritance and gene content of CNVs, and consultation with an online Database of Genomic Variants (DGV) and Online Mendelian Inheritance in Men (OMIM) for information on the genes involved. Our study suggests that genomewide oligonucleotide arrays such as the OaCGH44K platform can be used as a powerful diagnostic tool for detection of genomic imbalances associated with unexplained mental retardation or syndromic autism spectrum disorders. It is interesting to note that a small number of common variants were revealed by OaCGH244K in some study subjects but not in their parents and that some inherited CNVs had altered breakpoints. Further investigations on these alterations may provide useful information for understanding the mechanism of CNVs. Hum Mutat 28(11),1124,1132, 2007. © 2007 Wiley-Liss, Inc. [source] Association of genomic imbalances with drug resistance and thermoresistance in human gastric carcinoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2003Holger Tönnies Abstract Therapy resistance is the major obstacle to advances in successful cancer treatment. To characterize chromosomal alterations associated with different types of acquired MDR and thermoresistance, we applied CGH to compare a unique panel of human gastric carcinoma cells consisting of the parental, drug-sensitive and thermosensitive cancer cell line EPG85-257P, the atypical MDR variant EPG85-257RNOV, the classical MDR subline EPG85-257RDB and their thermoresistant counterparts EPG85-257P-TR, EPG85-257RNOV-TR and EPG85-257RDB-TR. CGH with genomic DNA prepared from these cell lines as probes successfully identified genomic gains and/or losses in chromosomal regions encoding putative genes associated with drug resistance and/or thermoresistance. These genes included various members of the families of ABC transporters and molecular chaperones. The importance of these cell variant-specific genomic imbalances in the development of MDR and thermoresistance is discussed and remains to be elucidated. © 2002 Wiley-Liss, Inc. [source] Holoprosencephaly: An update on cytogenetic abnormalities,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Claude Bendavid Abstract Holoprosencephaly (HPE), the most common developmental defect of the forebrain and midface, is caused by a failure of midline cleavage early in gestation. Isolated HPE, which is highly genetically heterogeneous, can be due to major chromosomal abnormalities. Initially, karyotype approach led to the identification of several recurrent chromosomal anomalies predicting different HPE loci. Subsequently, several genes were isolated from these critical HPE regions, but point mutations and deletions in these genes were found only in 25% of the genetic cases. In order to identify other HPE genes, a more accurate investigation of the genome in HPE patients was necessary. To date, high-resolution cytogenetic techniques such as subtelomeric multiplex ligation-dependent probe amplification (MLPA) and microarray-based comparative genomic hybridization (array CGH) have enhanced chromosomal aberration analysis. In this article, we have updated the cytogenetic anomalies associated with HPE in a map listing all the subtelomeric and interstitial deletions that have been characterized either by karyotype, MLPA, or array CGH. The accumulation of recurrent genomic imbalances will lead to the further delineation of minimal critical HPE loci, which is the first step to the identification of new HPE genes. © 2010 Wiley-Liss, Inc. [source] | |||||||||||||