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Results for “Comparative Genomics”

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PubMed1999

Loss of chromosome 13 is the most frequent genomic imbalance in malignant fibrous histiocytomas. A comparative genomic hybridization analysis of a series of 30 cases.

Regional chromosome localizations of DNA copy number imbalances were studied by comparative genomic hybridization in 30 malignant fibrous histiocytomas: 13 primary tumors (2 myxoid, 9 storiform pleomorphic, and 2 with more undifferentiated phenotype) and 17 local recurrences (2 myxoid, 11 storiform pleomorphic, and 4 with more undifferentiated phenotype). Abnormal comparative genomic hybridization (CGH) profiles were observed in 25 tumors (83%). The most frequent gains (ratio > 1.2) corresponded, by order of frequency, to entire Xp, and bands 1q21, 19q13.1, 19p13, 5p13-p14, 1p31, 17p, 18p, 20q, 1p35, 17q23, and 22q12. High levels of gains (ratio > 1.5) were recurrently detected for Xp (10 cases), and in bands 1q21-q22 (8 cases), 3q27 (4 cases), 5p13-p14 (3 cases), 13q32-q34 (3 cases), 15q22-q26 (3 cases), and 17p11-p12 (3 cases). Losses of 13q12-q14 or 13q21 were observed in a large proportion of tumors (17 cases), suggesting that a gene localized in this region could act as a tumor suppressor gene. Losses of 11q23, 2q32, 11p13, 10p, 1q4, 9p2, 16q12, 4q3, 10q25, 3p23, 2p24, and 12p were also recurrently observed. Taken together, these results provide an overview of chromosome imbalances present in MFH, which could be of use for diagnostic purposes. They point to various chromosome regions which may harbor genes important for malignant fibrous histiocytomas (MFH) oncogenesis and progression.

Chromosome Aberrations↗

PubMed2005

Detection of chromosomal abnormalities by comparative genomic hybridization.

PURPOSE OF REVIEW: Comparative genomic hybridization (CGH) is a modified in-situ hybridization technique. In this type of analysis, two differentially labeled genomic DNAs (study and reference) are cohybridized to normal metaphase spreads or to microarray. Chromosomal locations of copy number changes in the DNA segments of the study genome are revealed by a variable fluorescence intensity ratio along each target chromosome. Thus, CGH allows detection and mapping of DNA sequence copy differences between two genomes in a single experiment. RECENT FINDINGS: Since its development, comparative genomic hybridization has been applied mostly as a research tool in the field of cancer cytogenetics to identify genetic changes in many previously unknown regions. It is also a powerful tool for detection and identification of unbalanced chromosomal abnormalities in prenatal, postnatal and preimplantation diagnostics. SUMMARY: The development of comparative genomic hybridization and increase in resolution analysis by using the microarray-based technique offer new information on chromosomal pathologies and thus better management of patients.

Chromosome Aberrations↗

PubMed1999

Inferring tree models for oncogenesis from comparative genome hybridization data.

Comparative genome hybridization (CGH) is a laboratory method to measure gains and losses of chromosomal regions in tumor cells. It is believed that DNA gains and losses in tumor cells do not occur entirely at random, but partly through some flow of causality. Models that relate tumor progression to the occurrence of DNA gains and losses could be very useful in hunting cancer genes and in cancer diagnosis. We lay some mathematical foundations for inferring a model of tumor progression from a CGH data set. We consider a class of tree models that are more general than a path model that has been developed for colorectal cancer. We derive a tree model inference algorithm based on the idea of a maximum-weight branching in a graph, and we show that under plausible assumptions our algorithm infers the correct tree. We have implemented our methods in software, and we illustrate with a CGH data set for renal cancer.

Chromosome Aberrations↗

PubMed2003

[Fundamental and applied aspects of comparative genomics of vertebrates].

The Human Genome Project stimulated the development of efficient strategies and relevant hardware for complete genome sequencing. The comparative genomic approach extends the possibilities of using the sequencing data to identify new genes or conserved regulatory regions by means of nucleotide sequence alignment of the particular regions of the mouse and human genomes, or to trace the evolutionary events resulting in the genome structure of modern mammals. The review focuses on the use of new molecular cytogenetic methods along with computer-aided analysis of the genomes in vertebrates. Several factors hindering data analysis are considered. The currently available information on gene evolution rate inferred from comparative genomic data is presented. The origin and evolution of the genomes of several species are discussed.

Animals↗

PubMed1999

Assessment of genomic imbalances in malignant fibrous histiocytomas by comparative genomic hybridization.

In order to investigate genomic imbalances, comparative genomic hybridization was applied to 20 malignant fibrous histiocytomas. Deletions were rare and found mainly in chromosomes 2q33-35, 4q32-qter, 8p, 9p21-pter, 12p and 19p, whereas, over-representations frequently affected chromosomes 3, 4q31, 5p, 6, 7, 14q22-ter, 18p, as well as, five distinct amplifications within the regions 12q12-15 and 15q24-qter. The total number of genetic imbalances per tumor was slightly increased in primary tumors when compared to relapses. No relationship was found between the patterns of gain and loss when compared to the histological subtype, tumor grading, the clinical outcome and the p53 mutation status.

Aneuploidy↗

PubMed1995

[Detection of DNA amplifications and deletions in oral squamous cell carcinoma cell lines by comparative genomic hybridization (CGH)].

Comparative genomic hybridization (CGH) has recently developed for surveying DNA sequence copy number in tumors. The purpose of this study is to find and map chromosomal regions with amplifications and deletions in oral cancers by CGH. The results were further compared to those obtained by Southern hybridization and fluorescence in situ hybridization to investigate the mechanism of CGH identifying the amplification of oncogenes. DNAs extracted from 17 oral squamous cell carcinoma cell lines were labeled with biotin and hybridized to a normal metaphase spread together with digoxigenin-labeled normal reference DNA. The relative intensities of tumor DNA (detected using FITC) and normal DNA (detected with rhodamine) were measured by fluorescence imaging analysis system. Recurrent loci for amplification were observed on 8q22-q26, 3q25-q27, 7p12, 11q13, 13q33, 14q, 15q and 20q13. Deletions were seen on 3p, 18q21, 5q21-q22, 7q31 and 8p. There was a strong concordance for amplification detected by the CGH and Southern hybridization methods. These results indicated that these loci may contain previously unknown genes. Thus, CGH provides a useful approach for rapid identification of putative oncogenes as well as finding specific genetic markers for oral cancers.

Carcinoma, Squamous Cell↗

PubMed1998

Analysis of hematologic diseases using conventional karyotyping, fluorescence in situ hybridization (FISH), and comparative genomic hybridization (CGH).

Comparative genomic hybridization (CGH) has been proven to be an important tool in interphase cytogenetics of solid tumors. Although, because of methodological implications, balanced aberrations are not detected by CGH, the technique has uncovered a variety of new and interesting imbalanced karyotype changes. However, only a few studies deal with its application to hematologic disorders, although this is a main topic of cytogenetics. The aim of our study was, therefore, to evaluate the usefulness of CGH in the examination of hematologic neoplasms. For this purpose, bone marrow aspirates of 33 patients with different hematologic disorders were examined with CGH and the results compared with conventional cytogenetics (CC) and fluorescence in situ hybridization (FISH). CGH showed chromosome changes in 8 of 33 cases. CC found balanced aberrations in 4 of 33 and unbalanced changes in 9 of 33 samples. Differences between CGH and CC in unbalanced aberrations were seen in four cases. In these samples, either the number of aberrant cells found by CC was low and, therefore, difficult to detect by CGH, or complex aberrations in different cell clones as seen in CC were lumped together as one karyotype by CGH. In one sample, CC was not capable of giving any results at all, whereas CGH showed trisomy 8. CGH was also helpful in defining the bands involved in the structural aberrations, which was difficult by CC in some cases because of the low quality of metaphase spreads. All results obtained by CGH were confirmed by FISH, whereas CC and FISH were discordant in one case. Although CGH was not able to detect all aberrations, it gave important additional information for the correct localization of the aberrations found in CC, and it was most helpful in samples not processed successfully in CC. These advantages would open up a new field of application for CGH not only for research, but also for diagnostic purposes.

Adult↗

PubMed2003

Abnormalities on 1q and 7q are associated with poor outcome in sporadic Burkitt's lymphoma. A cytogenetic and comparative genomic hybridization study.

Comparative genomic hybridization (CGH) studies have demonstrated a high incidence of chromosomal imbalances in non-Hodgkin's lymphoma. However, the information on the genomic imbalances in Burkitt's Lymphoma (BL) is scanty. Conventional cytogenetics was performed in 34 cases, and long-distance PCR for t(8;14) was performed in 18 cases. A total of 170 changes were present with a median of four changes per case (range 1-22). Gains of chromosomal material (143) were more frequent than amplifications (5) or losses (22). The most frequent aberrations were gains on chromosomes 12q (26%), Xq (22%), 22q (20%), 20q (17%) and 9q (15%). Losses predominantly involved chromosomes 13q (17%) and 4q (9%). High-level amplifications were present in the regions 1q23-31 (three cases), 6p12-p25 and 8p22-p23. Upon comparing BL vs Burkitt's cell leukemia (BCL), the latter had more changes (mean 4.3 +/- 2.2) than BL (mean 2.7 +/- 3.2). In addition, BCL cases showed more frequently gains on 8q, 9q, 14q, 20q, and 20q, 9q, 8q and 14q, as well as losses on 13q and 4q. Concerning outcome, the presence of abnormalities on 1q (ascertained either by cytogenetics or by CGH), and imbalances on 7q (P=0.01) were associated with a short survival.

Adolescent↗

PubMedDate not supplied

Chromosomal localization of DNA amplifications in neuroblastoma tumors using cDNA microarray comparative genomic hybridization.

Conventional comparative genomic hybridization (CGH) profiling of neuroblastomas has identified many genomic aberrations, although the limited resolution has precluded a precise localization of sequences of interest within amplicons. To map high copy number genomic gains in clinically matched stage IV neuroblastomas, CGH analysis using a 19,200-feature cDNA microarray was used. A dedicated (freely available) algorithm was developed for rapid in silico determination of chromosomal localizations of microarray cDNA targets, and for generation of an ideogram-type profile of copy number changes. Using these methodologies, novel gene amplifications undetectable by chromosome CGH were identified, and larger MYCN amplicon sizes (in one tumor up to 6 Mb) than those previously reported in neuroblastoma were identified. The genes HPCAL1, LPIN1/KIAA0188, NAG, and NSE1/LOC151354 were found to be coamplified with MYCN. To determine whether stage IV primary tumors could be further subclassified based on their genomic copy number profiles, hierarchical clustering was performed. Cluster analysis of microarray CGH data identified three groups: 1) no amplifications evident, 2) a small MYCN amplicon as the only detectable imbalance, and 3) a large MYCN amplicon with additional gene amplifications. Application of CGH to cDNA microarray targets will help to determine both the variation of amplicon size and help better define amplification-dependent and independent pathways of progression in neuroblastoma.

Algorithms↗

PubMed2005

Deletion at chromosome band 20p12.1 in colorectal cancer revealed by high resolution array comparative genomic hybridization.

Array comparative genomic hybridization (Array CGH) with tiling path resolution for a approximately 4.61 Mb region of chromosome band 20p12.1 has been used to investigate copy number loss in 48 colorectal cancer cell lines and 37 primary colorectal cancers. A recurrent deletion was detected in 55% of cell lines and 23% of primary cancers and the consensus minimum region of loss was identified as a approximately 190 kb section from 14.85 Mb to 15.04 Mb of chromosome 20. Two noncoding RNA genes located in the region, BA318C17.1 and DJ974N19.1, were investigated by mutation analysis and real-time PCR in colorectal cancer cell lines. Sequence changes in BA318C17.1 and reduced expression of both genes was detected, suggesting that the abrogation of these genes may play a role in colorectal tumorigenesis.

Cell Line, Tumor↗

PubMedDate not supplied

Meta-analysis and pooled re-analysis of copy number changes in colorectal cancer detected by comparative genomic hybridization.

BACKGROUND: Comparative genomic hybridization (CGH) provides an insight into chromosomal changes associated with colorectal cancer (CRC) development. However, a problem with many studies is the limited cohort size, making the significance of some findings unclear. MATERIALS AND METHODS: To derive a better insight into the chromosomal changes associated with CRC, we performed a meta-analysis and pooled re-analysis of published metaphase CGH data. RESULTS: In addition to recurrent alterations, gains of 20 13q, 8q and 7p and loss of 18, 17p, 8p and 4p, pooling identified less frequent, but significant changes, including gain of 1q and 3, and losses from 6q, 9p and 21q. CONCLUSION: These additional alterations may be characteristic of some tumors and thus have relevance to CRC biology. Meta-analysis not only has the potential to detect novel changes, present at low frequency in several independent studies, but can provide greater reliability for their detection than single studies alone.

Adenoma↗

PubMed1997

Objective aneuploidy detection for fetal and neonatal screening using comparative genomic hybridization (CGH).

Comparative genomic hybridization (CGH) allows entire genomes to be scanned for whole and segmental aneuploidy and thus may be an appropriate tool for the detection of clinically important abnormalities during fetal and neonatal screening. Criteria to distinguish between significant aberrations and experimental artifacts are essential for these applications. This report describes the use of a t-statistic to detect changes in CGH profiles that differ significantly from variations that occur in CGH profiles of normal samples. Eleven cell lines derived from fetal or neonatal patients were analyzed in this study. Aneuploidies in these lines included trisomies for chromosomes 13, 16, 18, and 21 and monosomy for distal 5p and tetrasomy 18p. Aneuploidy was detected in all samples by using the t-statistic, although the extent of the aneuploid region was not correctly estimated in some cases. A detailed description of the t-statistic fused for making these CGH comparisons is described in a companion paper (Moore et al., Cytometry 28:183-190, 1997.

Aneuploidy↗

PubMed2000

[Correlation of DNA copy number changes to malignancy in oral squamous cell carcinomas by comparative genomic hybridization].

To compare clinical and histopathological findings to tumor DNA copy number changes, comparative genomic hybridization (CGH) was performed on 18 primary oral squamous cell carcinomas. Copy number increases were most frequently observed on 8q, 3q, 13q, 11p, and 11q, while copy number decreases most frequently on 10q, 1p, 18q, 9p, and 19q. Copy number changes in relationship to WHO grading were examined with the result that DNA copy number increase on chromosome 6p23-25 was characteristically observed in the groups of Grade II and Grade III, and DNA copy number decreases on chromosomes 9p21 and 11p11-13 were observed in the same groups. Furthermore, comparison of DNA copy number changes to TNM classification indicated that the decreases on chromosomes 1p36 and 10q25-26 might be related to tumor progression. Moreover, the relationship of DNA amplification or deletion to metastasis was investigated. It was found that the majority of the metastasis-positive tumors showed increases on 3q26 and 17q12-21 and showed decreases on chromosome 18q21. The data suggested that these DNA copy number changes on each chromosome in the three categories might be associated with tumor cell differentiation, tumor size, and lymph node metastasis.

Adult↗

PubMed2001

Identification and analysis of sex chromosomes by comparative genomic hybridization (CGH).

Comparative Genome Hybridization (CGH) can be used as a universal method for the identification of molecularly differentiated sex chromosomes. This is profitable in species with homomorphic sex chromosomes or when chromosomes are unfavourable for cytogenetics, e.g. when size differences are insufficient, chromosomes numerous and/or banding methods fail. In this method, genomic DNA from females competes as a probe with that from males for binding to the chromosome targets. Easy extraction and labelling methods afford a method that can be applied even when few specimens are available, e.g. when specimens for investigation have to be collected in the field - CGH also offers the possibility to obtain a rough estimate of the DNA composition of the sex chromosome.

Animals↗

PubMed2002

Genetic abnormalities detected in ependymomas by comparative genomic hybridisation.

Using comparative genomic hybridisation, we have analysed genetic imbalance in a series of 86 ependymomas from children and adults. Tumours were derived from intracranial and spinal sites, and classified histologically as classic, anaplastic or myxopapillary. Ependymomas showing a balanced profile were significantly (P<0.0005) more frequent in children than adults. Profiles suggesting intermediate ploidy were common (44% of all tumours), and found more often (P<0.0005) in tumours from adults and the spinal region. Loss of 22q was the most common specific abnormality, occurring in 50% of spinal (medullary) ependymomas and 26% of tumours overall. Genetic profiles combining loss of 22q with other specific abnormalities--gain of 1q, loss of 6q, loss of 10q/10, loss of 13, loss of 14q/14--varied according to site and histology. In particular, we showed that classic ependymomas from within the cranium and spine have distinct genetic profiles. Classic and anaplastic ependymomas with gain of 1q tended to occur in the posterior fossa of children and to behave aggressively. Our extensive data on ependymomas demonstrate significant associations between genetic aberrations and clinicopathological variables, and represent a starting point for further biological and clinical studies.

Adolescent↗

PubMedDate not supplied

Clinical applications of comparative genomic hybridization.

PURPOSE: Comparative genomic hybridization (CGH) is a powerful DNA-based cytogenetic technique that allows the entire genome to be scanned for chromosomal imbalances without requiring the sample material to be mitotically active. During the past 2 years we received many requests from various medical centers around the country to use CGH to resolve the identity of aberrant chromosomal material. METHODS: We report the use of CGH for the evaluation of 12 clinical postnatal cases in which traditional cytogenetic analysis yielded ambiguous results. This series consisted of five marker chromosomes, five unbalanced translocations, and two intrachromosomal duplications. RESULTS: Identification and characterization of the additional unknown chromosomal material was achieved with use of CGH. All CGH findings were validated by traditional fluorescence in situ hybridization and other specialized staining techniques. CONCLUSLONS: These results demonstrate the effective use of CGH as a focused, single-step method for the identification of chromosomal material of unknown origin.

Adolescent↗

PubMed2004

Statistical methods for detecting genomic alterations through array-based comparative genomic hybridization (CGH).

Array-based comparative genomic hybridization (ABCGH) is an emerging high-resolution and high-throughput molecular genetic technique that allows genome-wide screening for chromosome alterations associated with tumorigenesis. Like the cDNA microarrays, ABCGH uses two differentially labeled test and reference DNAs which are cohybridized to cloned genomic fragments immobilized on glass slides. The hybridized DNAs are then detected in two different fluorochromes, and the significant deviation from unity in the ratios of the digitized intensity values is indicative of copy-number differences between the test and reference genomes. Proper statistical analyses need to account for many sources of variation besides genuine differences between the two genomes. In particular, spatial correlations, the variable nature of the ratio variance and non-Normal distribution call for careful statistical modeling. We propose two new statistics, the standard t-statistic and its modification with variances smoothed along the genome, and two tests for each statistic, the standard t-test and a test based on the hybrid adaptive spline (HAS). Simulations indicate that the smoothed t-statistic always improves the performance over the standard t-statistic. The t-tests are more powerful in detecting isolated alterations while those based on HAS are more powerful in detecting a cluster of alterations. We apply the proposed methods to the identification of genomic alterations in endometrium in women with endometriosis.

Chromosome Aberrations↗

PubMed1997

Automatic correction of the interfering effect of unsuppressed interspersed repetitive sequences in comparative genomic hybridization analysis.

Comparative genomic hybridization (CGH) is a relatively new technique whose application is increasing. The method has mostly been employed for detection of chromosome aberrations in cancers, and a large amount of data in this field is accumulating. At the same time, efforts are made to improve the technique in order to increase the sensitivity and the generation of reliable results. Based on experimental data, we have developed a computer algorithm for eliminating some of the interfering effects of unsuppressed repetitive sequences in CGH analysis, and thereby improved our CGH analysis system.

Algorithms↗