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PubMed2004

Cytogenetic investigation of testicular carcinoma in situ and early seminoma by high-resolution comparative genomic hybridization analysis of subpopulations flow sorted according to DNA content.

Interpretation of data from comparative genomic hybridization (CGH) analysis of testicular neoplasms located within normal parenchyma is complicated, because the results may be influenced by a heterogeneity of subpopulations with different chromosomal aberrations and ploidy. In this study, therefore, early stages of testicular germ cell neoplasia were cytogenetically analyzed after flow sorting of nuclei according to their DNA ploidy. DNA from subpopulations with different ploidy was globally amplified by means of degenerate oligonucleotide primed polymerase chain reaction, labeled with FITC-dCTP and -dUTP by nick translation, and analyzed with high resolution CGH. A characteristic pattern of chromosomal abnormalities associated with testicular germ cell cancer (gains in 1q, 7, 8, 12, 14, 21, X; losses from 4, 5, 9, 11, 13, 18, Y) was observed in the tri- to hexaploid but not in the hyperdiploid or in pure tetraploid subpopulations. Our data suggest that subpopulations with a triploid to hexaploid DNA content purified from testes with germ cell neoplasia harbor a mixture of overt tumor and carcinoma-in-situ cells (CIS) and DNA content of CIS cells being in the triploid to hypotetraploid range, supporting the current theory of polyploidization as one of the first events of malignant transformation.

Carcinoma↗

PubMed1997

Image analysis for comparative genomic hybridization based on a karyotyping program for windows.

OBJECTIVE: To describe the image processing and analysis techniques we developed for the quantitative analysis of comparative genomic hybridization (CGH). STUDY DESIGN: A system for CGH cytometry is based on a semiautomated karyotyping program using the Windows graphic user interface. RESULTS: After alignment and normalization of the fluorescence images of the test genome (FITC) and reference genome (TRITC), the chromosomes are segmented and arranged as a CGH karyogram. The CGH karyograms from different metaphases of one tumor sample are represented as a CGH sum karyogram. Mean DAPI, FITC, TRITC and RATIO images, as well as ratio profiles with the 95% confidence interval, can be displayed. CONCLUSION: Representation of CGH results in the form of pseudocolored mean ratio chromosomes enhances the visibility of the method. The ratio profile plus confidence interval facilitates the identification of preparation artifacts and the classification of chromosomal imbalances. The sum karyograms of several tumors can be combined into a CGH superkaryogram of a tumor subgroup; that helps identify recurrent DNA changes in a tumor and might lead to genetic tumor classification based on CGH.

DNA, Neoplasm↗

PubMed2005

Comparative genomic hybridization analysis of spontaneous abortion.

OBJECTIVES: To evaluate the feasibility and superiority of comparative genomic hybridization (CGH) in the genetic analysis of spontaneously aborted tissues. METHODS: 38 conceptuses from early failed pregnancies were studied, of which, 27 samples were fresh and 11 were old. Each sample was divided into two parts, one part for conventional cytogenetic analysis and the other for CGH analysis. RESULTS: All 38 spontaneously aborted tissues were analyzed successfully by the CGH approach, but only 31 samples received results from the cytogenetic karyotype analysis, while 7 other tissues failed to get data due to failure in tissue culturing. Among the specimen successfully analyzed by both approaches, 90% (28 out of 31) obtained identical results, and 14 aneuploidies were found. The only structural chromosome aberration in this series, 46, XY, del(3) (q22-24), was found using the CGH approach, which appeared as a normal male karyotype on the chromosomal metaphase spread. Also, two cases indicated triploidies under cytogenetic analysis but appeared to be normal on the CGH profile. In addition, among the seven samples of tissue culture failure, CGH identified three to be aneuploidies. CONCLUSION: The CGH analysis accurately identifies chromosomal unbalanced abnormalities related to spontaneous abortions with low failure rate.

Aborted Fetus↗

PubMed2003

A case of nasal leiomyosarcoma: the first comparative genomic hybridization analysis.

Leiomyosarcomas are rare in the head and neck region. The treatment of choice is surgical resection. We present a case of leiomyosarcoma in a 50-year-old female patient, arising from the inferior turbinate. The tumor was resected by a transnasal microendoscopic approach and no evidence for tumor recurrence was found during an endoscopic and radiologic follow-up of two years. Cytogenetic analysis by means of comparative genomic hybridization revealed chromosomal gains at 4p13p15, 6p21p22, 7q22qter, 9q22qter and chromosomal losses at 10q22qter and 19p12p13.1. With augmented experience, the transnasal approach may be appropriate to resect circumscribed malignant tumors located in the nasal cavity.

Chromosome Aberrations↗

PubMed1999

Improved sensitivity in comparative genomic hybridization analysis of DNA heteroploid cell mixtures after pre-enrichment of subpopulations by fluorescence activated cell sorting.

Cytogenetic analysis of solid tumors with comparative genomic hybridization (CGH) is hampered by the dilution of DNA from individual tumor subpopulations with DNA from other cells. We investigated to what extent this dilution effect can be alleviated using fluorescence activated cell sorting (flow sorting) of experimental DNA heteroploid cell mixtures prior to CGH. From mixtures of normal lymphocytes with triploid K-562 cells the individual components were sorted according to stemline DNA content and processed by CGH in comparison with pure K-562 samples and the original mixtures. Compared with 30 autosome copy number imbalances found in pure K-562 samples, a mixture with 32% K-562 cells showed 16 imbalances, and none were detected in mixtures with 13% or 5% K-562 cells. In contrast, 29, 22 and 23 imbalances were detected in K-562 nuclei sorted from the 32%, 13% and 5% mixtures, respectively. This indicate that CGH analysis of flow sorted DNA aneuploid subpopulations enables a specific cytogenetic analysis of the individual subclones in a DNA heteroploid cell population.

Cell Separation↗

PubMed2005

Comparative genomic hybridization analysis for pancreatic cancer specimens obtained by endoscopic ultrasonography-guided fine-needle aspiration.

BACKGROUND: Comparative genomic hybridization (CGH) analysis of pancreatic cancer has been done exclusively for surgical and autopsy specimens, because of the difficulty of tissue sampling without surgery. To overcome this difficulty, we applied CGH technology to cells obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). METHODS: In the present study, we performed EUS-FNA for 17 patients with pancreatic cancer before surgery. Tumor cells were selected by microdissection. DNA was extracted from the cells and amplified by degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR). Then CGH was carried out. RESULTS: In the 15 patients with tubular adenocarcinoma, the most common loci of gains (including amplification) were 5p, 8q, and 20q (60% of the patients); and 1q, 7p, and 12p (27%). The most frequent losses were 17p (73%); 9p, 18q, and 19p (47%); and 8p (33%). These findings were similar to our previously reported data. Both of the patients with acinar cell carcinoma showed gains of 2q and 5p, and losses of 1p, 9p, 9q, 11p, 11q, 14q, 17p, 17q, and 18q. CONCLUSIONS: The results of this study suggest that comprehensive genetic analysis is possible for EUS-FNA biopsy specimens, with a combination of microdissection and DOP-PCR. This analytical strategy will enable us to evaluate the biological characteristics of pancreatic cancer before treatment.

Adenocarcinoma↗

PubMed2002

Challenges for biomedical informatics and pharmacogenomics.

Pharmacogenomics requires the integration and analysis of genomic, molecular, cellular, and clinical data, and it thus offers a remarkable set of challenges to biomedical informatics. These include infrastructural challenges such as the creation of data models and databases for storing these data, the integration of these data with external databases, the extraction of information from natural language text, and the protection of databases with sensitive information. There are also scientific challenges in creating tools to support gene expression analysis, three-dimensional structural analysis, and comparative genomic analysis. In this review, we summarize the current uses of informatics within pharmacogenomics and show how the technical challenges that remain for biomedical informatics are typical of those that will be confronted in the postgenomic era.

Communication↗

PubMed2001

Comparative genomic hybridization analysis of transitional cell carcinomas of the renal pelvis.

We used comparative genomic hybridization to analyze 10 primary tumor samples from patients with transitional cell carcinoma of the renal pelvis. The most frequent loss was located at 9q, that is, in 50% of the tumors. Gains of DNA sequences were most frequently observed in chromosome regions 1q21 approximately q23, 2p23 approximately p25, 8q21.1 approximately q22 and in the whole chromosome 20. High level amplifications at 1q21 approximately q25, 6p22 approximately p23, 8q21 approximately q22, 8q22 approximately q24.1, 11q13, and 12q14 approximately q21 were detected. Most of these regions have previously been reported to be involved in transitional cell carcinoma of the bladder, thus confirming the importance of an increasing number of chromosome imbalances in the development and progression of this type of tumors.

Aged↗

PubMed2006

Increased susceptibility to maternal aneuploidy demonstrated by comparative genomic hybridization analysis of human MII oocytes and first polar bodies.

Single cell comparative genomic hybridization (CGH) was employed to extensively investigate 24 unfertilized or in vitromatured meiosis II oocytes and their corresponding first polar bodies (PBs), to determine how and whether all 23 chromosomes participate in female meiosis I errors and to accurately estimate the aneuploidy rate in the examined cells. Results were obtained for 15 oocytes and 16 PBs, representing 23 eggs (MII oocyte-PB complexes) donated from 15 patients (average age 32.2 years). Abnormalities were detected in ten eggs, giving an overall aneuploidy rate of 43.5%. In all, fourteen anomalies were scored, with the fertilized oocyte being at risk of monosomy in eight cases and at risk of trisomy in six; chromosomes of various sizes participated. CGH was able to give a comprehensive aneuploidy rate, as both absence of chromosomal material and the presence of extra copies were accurately scored. The aneuploidy mechanisms determined were: classical whole univalent non-disjunction; chromatid predivision prior to anaphase I, leading to metaphase II imbalance. There was also evidence of germinal mosaicism for a trisomic cell line. Three patients appeared to be predisposed to meiosis I errors, based on the presence of either multiple abnormalities in one or more of their examined cells, or of the same type of abnormality in all of their cells. Exclusion of these susceptible patients reduces the aneuploidy rate to 20%. Various hypotheses are put forward to explain these observations in order to stimulate research into the complex nature of female meiotic regulation.

Adult↗

PubMed1997

Comparative genomic hybridization analysis detects frequent, often high-level, overrepresentation of DNA sequences at 3q, 5p, 7p, and 8q in human non-small cell lung carcinomas.

Comparative genomic hybridization analysis was used to identify chromosomal imbalances in 20 non-small cell lung carcinoma (NSCLC) biopsies and cell lines. The chromosome arms most often overrepresented were 3q (85%), 5p (70%), 7p (65%), and 8q (65%), which were observed at high copy numbers in many cases. Other common overrepresented sites were 1q, 2p, and 20p. DNA sequence amplification was often observed, with the most frequent site being 3q26 (six cases). Other recurrent sites of amplification included 8q24, 3q13, 3q28-qter, 7q11.2, 8p11-12, 12p12, and 19q13.1-13.2. The most frequent underrepresented segment was 3p21 (50%); other recurrent sites of autosomal loss included 8p21-pter, 15q11.2-13, 5q11.2-15, 9p, 13q12-14, 17p, and 18q21-qter. These regions of copy number decreases are also common sites of allelic loss, further implicating these sites as locations of tumor suppressor genes. Although some of the overrepresented segments harbor known or suspected oncogenes/growth-regulatory genes, we have identified 3q and 5p as new sites that are very frequently overrepresented in NSCLC. These findings could represent entry points for the identification of novel amplified DNA sequences that may contribute to the development or progression of NSCLC.

Biopsy↗

PubMed1998

Characterisation of a collecting duct carcinoma by cytogenetic analysis and comparative genomic hybridisation.

Collecting duct carcinoma (CDC) is a rare variant of carcinoma of the kidney with aggressive behaviour. CDC arise from the epithelium of the ducts of Bellini in the distal nephron. A CDC in a 53-year old male patient is characterised both by cytogenetic analysis and comparative genomic hybridisation (CGH). The cytogenetic analysis shows a biclonal karyotype 47,XY,+3[2]/40-44,XY,-12[3], -22[4][cp5]/46,XY[42]. Loss of DNA sequences detected by CGH involves chromosome 1, 2, 9, 11 and 18. Gain of DNA sequences affect chromosome 16 and 20. The characterisation of a CDC in this study represents an additional contribution to the poorly explored CDC.

Adult↗

PubMed1997

Comparative genomic hybridization analysis of Wilms tumors.

In this study we have applied the technique of comparative genomic hybridization (CGH) to a large series of sporadic Wilms tumors, including six samples of the associated nephroblastomatosis. The data obtained were compared with the findings of molecular studies carried out on the same material. The aims of the study were (1) to characterize the range of genetic variation in sporadic Wilms tumor and nephroblastomatosis, (2) to determine whether changes could be found that have not been detected by commonly used techniques, and (3) to compare the sensitivity of CGH with that of conventional molecular analysis. The chromosomes that showed gains and losses by CGH were similar to those previously found in molecular and cytogenetic studies, however loss of 4q was a new event identified in 2 out of 46 tumors. We did not detect amplified genetic material. Comparison of the data from the nephroblastomatosis and tumor samples from the same patient showed that loss of 7p may be associated with malignant transformation, and that losses in 1p, 11p, 4q and gains in 1q and 12q can be early events; whilst loss in 9p and gain of 8, 10q and 18 are possible secondary changes in tumor development. The combined CGH and molecular techniques used demonstrated involvement of two specific 1p regions in the etiology of Wilms tumor.

Chromosome Aberrations↗

PubMed1998

Detection of chromosomal gains and losses in comparative genomic hybridization analysis based on standard reference intervals.

Criteria for detection of chromosome aberrations by Comparative Genomic Hybridization (CGH) are not standardized and improvement of this part of the analysis is of paramount importance to the applicability of the technique. The aim of this work was to suggest CGH detection criteria that increase the specificity and sensitivity and at the same time include chromosome regions previously excluded from CGH analysis. We analyzed 33 hybridizations with normal DNA and modified our CGH software in order to use a selection of these normal analyses as a model for interpretation of analyses of unknown samples. This approach was successfully tested on 14 samples with known aberrations.

Chromosome Aberrations↗

PubMed2003

A novel complexity measure for comparative analysis of protein sequences from complete genomes.

Analysis of sequence complexities of proteins is an important step in the characterization and classification of new genomes. A new measure has been proposed to compute sequence complexity in protein sequences based on linguistic complexity. The algorithm requires a single parameter, is computationally simple and provides a framework for comparative genomic analysis. Protein sequences were classified into groups of high or low complexity based on a quantitative measure termed F(c), which is proportional to the fraction of low complexity sequence present in the protein. The algorithm was tested on sequences of 196 non-homologous proteins whose crystal structures are available at </=2.0 A resolution. Protein sequences of high complexity had 'globular' structures (95% agreement), whereas those of low complexity had non-globular structures (80% agreement). Application of this measure to proteins of unknown structure/function from different genomes revealed that the sequences of high complexity constitute the majority in all genomes (about 90% in Archaea, about 93% in Eubacteria, 89% in Saccharomyces cerevisiae and 90% in Caenorhabditis elegans). Aeropyrum pernix among Archaeae and Deinococcus radiodurans among Eubacteria have the lowest fraction of high complexity proteins (75% and 80% respectively). Further, it was observed that a few bacterial pathogens (Mycobacterium tuberculosis, Pseudomonas aeruginosa) have high fraction of low complexity proteins. The program ScanCom is available from the authors as a PERL script (UNIX system).

Algorithms↗

PubMed2005

Identification of a novel homozygous deletion region at 6q23.1 in medulloblastomas using high-resolution array comparative genomic hybridization analysis.

PURPOSE: The aim of this study is to comprehensively characterize genome copy number aberrations in medulloblastomas using high-resolution array comparative genomic hybridization. EXPERIMENTAL DESIGN: High-density genomic arrays containing 1,803 BAC clones were used to define recurrent chromosomal regions of gains or losses throughout the whole genome of medulloblastoma. A series of 3 medulloblastoma cell lines and 16 primary tumors were investigated. RESULTS: The detected consistent chromosomal aberrations included gains of 1q21.3-q23.1 (36.8%), 1q32.1 (47.4%), 2p23.1-p25.3 (52.6%), 7 (57.9%), 9q34.13-q34.3 (47.4%), 17p11.2-q25.3 (89.5%), and 20q13.31-q13.33 (42.1%), as well as losses of 3q26.1 (57.9%), 4q31.23-q32.3 (42.1%), 6q23.1-25.3 (57.9%), 8p22-23.3 (79%), 10q24.32-26.2 (57.9%), and 16q23.2-q24.3 (63.2%). One of the most notable aberrations was a homozygous deletion on chromosome 6q23 in the cell line DAOY, and single copy loss on 30.3% primary tumors. Further analyses defined a 0.887 Mbp minimal region of homozygous deletion at 6q23.1 flanked by markers SHGC-14149 (6q22.33) and SHGC-110551 (6q23.1). Quantitative reverse transcription-PCR analysis showed complete loss of expression of two genes located at 6q23.1, AK091351 (hypothetical protein FLJ34032) and KIAA1913, in the cell line DAOY. mRNA levels of these genes was reduced in cell lines D283 and D384, and in 50% and 70% of primary tumors, respectively. CONCLUSION: Current array comparative genomic hybridization analysis generates a comprehensive pattern of chromosomal aberrations in medulloblastomas. This information will lead to a better understanding of medulloblastoma tumorigenesis. The delineated regions of gains or losses will indicate locations of medulloblastoma-associated genes. A 0.887 Mbp homozygous deletion region was newly identified at 6q23.1. Frequent detection of reduced expression of AK091351 and KIAA1913 genes implicates them as suppressors of medulloblastoma tumorigenesis.

Adolescent↗

PubMed2004

Evolutionary relationships of Fusobacterium nucleatum based on phylogenetic analysis and comparative genomics.

BACKGROUND: The phylogenetic position and evolutionary relationships of Fusobacteria remain uncertain. Especially intriguing is their relatedness to low G+C Gram positive bacteria (Firmicutes) by ribosomal molecular phylogenies, but their possession of a typical gram negative outer membrane. Taking advantage of the recent completion of the Fusobacterium nucleatum genome sequence we have examined the evolutionary relationships of Fusobacterium genes by phylogenetic analysis and comparative genomics tools. RESULTS: The data indicate that Fusobacterium has a core genome of a very different nature to other bacterial lineages, and branches out at the base of Firmicutes. However, depending on the method used, 35-56% of Fusobacterium genes appear to have a xenologous origin from bacteroidetes, proteobacteria, spirochaetes and the Firmicutes themselves. A high number of hypothetical ORFs with unusual codon usage and short lengths were found and hypothesized to be remnants of transferred genes that were discarded. Some proteins and operons are also hypothesized to be of mixed ancestry. A large portion of the Gram-negative cell wall-related genes seems to have been transferred from proteobacteria. CONCLUSIONS: Many instances of similarity to other inhabitants of the dental plaque that have been sequenced were found. This suggests that the close physical contact found in this environment might facilitate horizontal gene transfer, supporting the idea of niche-specific gene pools. We hypothesize that at a point in time, probably associated to the rise of mammals, a strong selective pressure might have existed for a cell with a Clostridia-like metabolic apparatus but with the adhesive and immune camouflage features of Proteobacteria.

Bacterial Proteins↗

PubMed2005

Large cell neuroendocrine carcinoma of the uterine cervix with cytogenetic analysis by comparative genomic hybridization: a case study.

Large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is a newly introduced category of the revised World Health Organization classification. We reported a case of cervical LCNEC with cytogenetic analysis by comparative genomic hybridization (CGH). The cervical tumor showed moderately increased mitotic activity (8-14 mitotic figures per 10 high-power fields) and focal necrosis, which made it problematic to differentiate from atypical carcinoid. CGH analysis failed to detect chromosome 11q loss that has been reported to be characteristic of pulmonary atypical carcinoids. Furthermore, chromosome 3q amplification, which has been detected frequently in pulmonary small cell carcinomas and LCNECs but not in pulmonary typical and atypical carcinoids, was the most remarkable chromosomal aberration. Although CGH reports are extremely rare in neuroendocrine tumors of the uterine cervix, specific chromosomal aberrations may be useful in their distinction.

Adult↗

PubMed2003

Comparative study of primary and recurrent ovarian serous carcinomas: comparative genomic hybridization analysis with a potential application for prognosis.

OBJECTIVES: The purpose of this study is to comparatively characterize genomic imbalances in primary and recurrent ovarian serous carcinomas and to identify genomic alterations that may be used as a marker for prognosis. METHODS: Twenty ovarian serous carcinomas were studied by comparative genomic hybridization (CGH). RESULTS: Genomic alterations were found in all of the tumors. The most common regions involving gain of DNA copy numbers are 1q41q44, 8q22q24, 19p12q13.1, 20q12q13, 3q26q29, 12p12p13, 2p22p25, 7p14p21, 5p15.2p15.3, and 17q22q25. The most common regions with loss of DNA copy numbers are Xp11.2q13, 4q31q35, Xp21p22.3, 18q22q23, 13q22q31, 9p22p24, and 16q22q24. High-level gains were detected at chromosomal regions of 1q41q44, 2p22p25, 3q26q29, and 19p12q13.1. Comparative analysis of primary and recurrent tumors showed that gains of 2p22p25, 19p12q13.1, and 20q12q13 and loss of 5q14q22 were more common in the recurrent high-grade tumors. About 85% of the tumors showed increases in DNA copy numbers in the regions (2p and 8q) harboring the myc family gene. Patients with tumor containing fewer than seven chromosomal aberrations showed longer survival time. CONCLUSION: The myc oncogene family may play a role in the pathogenesis of ovarian serous carcinomas. Our study suggests that tumors with gains of 2p22p25, 19p12q13.1, and 20q12q13 and loss of 5q14q22 may be at high risk for recurrence. Furthermore, the patients' survival time inversely correlates with the numbers of chromosomal alterations found in their tumors. CGH analysis may have a clinical application in predicting prognosis and risk of recurrence in patients with ovarian serous carcinomas.

Aged↗