Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Genomic instability”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 541 records · Page 30Linked to original sources
PubMed1999

Genomic instability in silica- and cadmium chloride-transformed BALB/c-3T3 and tumor cell lines by random amplified polymorphic DNA analysis.

Our earlier studies using random amplified polymorphic DNA (RAPD) analysis have shown genetic instability in human lung cancer tissues. Here we have investigated the potential for genetic instability in silica- and cadmium chloride (CdCl2)-transformed BALB/c-3T3 cell lines. Non-transformed, transformed BALB/c-3T3 cells, and tumor cell lines (obtained by injecting nude mice with transformed cell lines) were analyzed for genomic changes. DNAs from 10 different transformed clones and their corresponding tumor cell lines were amplified individually by RAPD analysis using 10 arbitrary primers. DNA from non-transformed BALB/c-3T3 cells was used as a control to compare genetic alterations, if any, between non-transformed, transformed and tumor cell populations. PCR products from RAPD were electrophoretically separated on agarose gels and the banding profiles were visualized by ethidium bromide staining. Five of the 10 primers tested revealed genomic changes in silica-transformed cell lines when compared to non-transformed BALB/c-3T3 cells. Comparison of all 10 transformed and tumor cell lines showed varied degrees of genomic changes using all 10 primers. CdCl2-transformed cell lines displayed fewer genomic changes, only three of 10 primers showed a positive result. CdCl2-transformed cells and their corresponding tumor cell lines showed specific banding pattern differences in six of the 10 samples tested with six of the 10 primers. Changes in band intensity were the most commonly observed changes both in silica- and CdCl2-transformed and tumor cell lines. The results seem to indicate a progressive change in genomic rearrangements which may directly or indirectly be associated with progression of tumorigenesis.

3T3 Cells↗
PubMed2001

Allelic loss and gain, but not genomic instability, as the major somatic mutation in primary hepatocellular carcinoma.

To identify genetic abnormalities in primary hepatocellular carcinoma (HCC), we performed microsatellite analysis (MSA) on 60 Chinese HCC specimens. Utilizing a semi-quantitative MSA and 292 highly polymorphic markers spanning all 22 autosomes, we found that somatic allelic imbalance (AI) occurred frequently in HCC. To evaluate the nature of the AI, comparative genomic hybridization was performed on 20 HCC specimens. The combined use of these two methods revealed frequent allelic loss on 17p, 9p21-p23, 4q, 16q21-q23.3, 13q, 8p21-p23, and 6q24-q27, whereas there was frequent allelic gain on 1q, 17q, and 8q24. The region with the highest incidence of genomic imbalance was 17p13 (65%), followed by 9p21-p23 (55%), 4q (35-51%), 16q21-q23.3 (52%), 17p12 (49%), 13q (39-46%), 8p21-p23 (41-45%), 8q24 (41%), and 1q32 (40%). In addition, aberrations of 19p13.3, 16p13.3, 13q33-q34, 9q13-31, and 7q were reported for the first time. The presence of a close correlation of 17p13 deletion with abnormalities of some other loci implies that 17p13 could play a crucial role in oncogenesis. Interestingly, microsatellite instability was rarely seen in our patients, in contrast to that observed in European HCC samples.

Adult↗
PubMed1997

Selection for genome instability by DNA damage in human cells: unstable microsatellites and their consequences for tumourigenesis.

The emergence of tumour cells resistant to chemotherapeutic treatment is a major confounding factor in anticancer treatment. Many chemotherapeutic drugs are DNA damaging agents. Resistance to DNA damage can be acquired via a plethora of different mechanisms, including, surprisingly, loss of DNA mismatch repair activity. The DNA mismatch repair system acts after DNA replication and corrects non-Watson-Crick base pairs and other replication errors. Human cells lacking mismatch repair activity have high spontaneous mutation rates. Frequent frameshift mutations in repetitive DNA sequences are characteristically associated with the defect. This hypermutability at repetitive sequences is termed microsatellite instability. DNA mismatch repair defects underlie a predisposition to cancer and are associated with a significant fraction of apparently sporadic cancer cases. In contrast to many other neoplasms, gross genetic aberrations are rare in cells from tumours with microsatellite instability. In these mismatch repair-defective tumours, certain genes that would normally hinder tumour development are frequently found to be inactivated by frameshift mutations in repetitive DNA tracts within their coding sequences. This implies that the small-scale genome alterations characteristic of mismatch repair defects can act as a driving force in tumour development.

Antineoplastic Agents↗
PubMed2000

Links between replication, recombination and genome instability in eukaryotes.

Double-strand breaks in DNA can be repaired by homologous recombination including break-induced replication. In this reaction, the end of a broken DNA invades an intact chromosome and primes DNA replication resulting in the synthesis of an intact chromosome. Break-induced replication has also been suggested to cause different types of genome rearrangements.

DNA Damage↗
PubMed2001

Centrosome abnormalities, genomic instability and carcinogenic progression.

Centrosome abnormalities are a frequent finding in various malignant tumors. Since centrosomes form the poles of the mitotic spindle, these abnormalities have been implicated in chromosome missegregation and the generation of aneuploid cells which is commonly found in many human neoplasms. It is a matter of debate, however, whether centrosome alterations can drive cells into aneuploidy or simply reflect loss of genomic integrity by other mechanisms. Since these two models have fundamentally different implications for the diagnostic and prognostic value of centrosome abnormalities, we will discuss the relevance of abnormal centrosomes in the context of different oncogenic events as exemplified by high-risk human papillomavirus-associated carcinogenesis.

Aneuploidy↗
PubMed2000

A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model.

Approximately 40% of human breast cancers contain alterations in the tumor suppressor p53. The p53 172R-H gain-of-function mutant (equivalent to the common 175R-H human breast cancer mutant) has been shown to promote aneuploidy and tumorigenesis in the mammary gland in transgenic mice and may affect genomic stability in part by causing centrosome abnormalities. The precise mechanism of action of these gain-of-function mutants is not well understood, and has been studied primarily in fibroblast cell lines. A novel p53-null mouse mammary epithelial cell line developed from p53-null mice has been used in adenovirus-mediated transient transfection experiments to study the properties of this p53 mutant. Marked centrosome amplification and an increased frequency of aberrant mitoses were observed within 72 h of introduction of p53 172R-H. However, few cells with aberrant centrosome numbers were observed in cells stably expressing the p53 172R-H mutant. Furthermore, stable expression of this p53 mutant reduced both basal and DNA damage-induced apoptosis. This result may be mediated in part through abrogation of p73 function. The p53 172R-H mutant, therefore, appears to influence tumorigenesis at the molecular level in two distinct ways: promoting the development of aneuploidy in cells while also altering their apoptotic response after DNA damage.

Amino Acid Substitution↗
PubMedDate not supplied

[Genome instability and neoplasia].

Necessity of oncogene for the neoplastic cell transformation is substantiated. The oncogene may be introduced into the cell by a virus; be present in the cell from its formation but be repressed by products of regulatory genes; be arisen from separated DNA segments. The latter possibility is discussed in view of data on the presence of mobile elements and Sarc sequences in the cell genome.

Animals↗
PubMed2002

Genomic instability in pituitary adenomas.

Pituitary adenomas most commonly are identified as small, incidental microadenomas. They however may progress to macroadenoma forming intra and later suprasellar tumors which in about 1/3 of cases invade surrounding structures at the time of diagnosis. Mechanism of pituitary tumorigenesis remains still elusive. Because the value of karyotyping is limited by the technical problems related to cytogenetic methods, we studied the spectrum of chromosomal imbalances associated with pituitary adenoma using comparative genomic hybridization (CGH). Copy number aberrations on all 22 autosomes were evaluated by CGH using advanced computer software. In total, fifteen patients were included in the study of 9 non-invasive, 4 invasive and two recurrent adenomas. The mean age of the patients were 48 years ranging from 36 to 68 years. Five tumors showed hormonal activity. The histogram of all 15 cases representing the DNA imbalances as an incidence curve along each chromosome showed losses particularly for chromosomes 1p, 2q, 4, 5, 6, 11q, 12q, 13q and 18q as well as overrepresentation on 9q, 16p, 17p, 19, 20q. Functioning adenomas carried more imbalances than non-functioning, specifically deletions on chromosome 4 and 18q as well as overrepresentations of chromosomes 17 and 19. Invasive adenomas carried more overrepresentations at 1p34 than non-invasive tumors. Recurrent adenomas harbored more alterations than primary tumors, particularly DNA gains. The primary data is accessible at our CGH online tumor database at http://amba.charite.de/cgh. Reviewing the existing literature on the genetics of pituitary adenoma and discussing our results in this context, we hope that our study will contribute to the knowledge of this neoplasm.

Adenoma↗
PubMed1998

Induction of chromosome aberrations and delayed genomic instability by photochemical processes.

Exponentially growing cells cultured in medium containing bromodeoxyuridine, then exposed to UVA light in the presence of the dye Hoechst 33258, show significant levels of DNA strand breaks and base damage. This dye-bromodeoxyuridine-UVA photolysis treatment is markedly cytotoxic. We now demonstrate that exposure of cells to the agents used in photolysis leads directly to the formation of chromosome aberrations. Furthermore, we demonstrate that this photochemical treatment induces delayed chromosomal instability in clonal populations derived from single progenitor cells surviving photolysis. These results suggest that photolysis-induced DNA damage leads to chromosome rearrangements that could account for the observed cytotoxicity. Furthermore, in those cells surviving photolysis, the delayed effects of this treatment can be observed several generations after exposure and are manifested as compromised genomic integrity.

Animals↗
PubMed1996

Genomic instability in MycER-activated Rat1A-MycER cells.

The deregulated expression of c-Myc protein is associated with the non-random locus-specific amplification of the dihydrofolate reductase (DHFR) gene. This study was performed to determine whether additional chromosomal aberrations occur when c-Myc protein levels are up-regulated for prolonged periods. To this end, we have used Rat1A-MycER cells, which allow the experimental regulation of Myc protein levels. We examined the genomic stability of Rat1A-MycER cells cultivated in either the absence or the presence of estrogen, which reportedly activates the chimeric MycER protein in these cells. Following prolonged periods of MycER activation, Rat1A-Mycer cells exhibited irreversible chromosomal aberrations. The aberrations included numerical changes, chromosome breakage, the formation of circular chromosomal structures, chromosome fusions, and extrachromosomal elements.

Animals↗
PubMed1995

Genomic instability involved in virus-related hepatocarcinogenesis.

In spite of the epidemiological link between the hepatitis C virus (HCV) infection and the incidence of hepatocellular carcinoma (HCC), there is currently no data to prove the direct oncogenicity of HCV. In this situation, we must consider not only the viral but also the nonviral factor which may accelerate hepatocarcinogenesis. Previously, we showed that a 60-bp subgenomic HBV DNA (15AB, nt 1555-1914 of HBV DNA) is a hot spot for the genomic recombination, and the cellular protein binding to 15AB may be the putative recombinogenic protein. In this paper, we show that the 15AB-like sequence exists in the human chromosomal DNA. The 15AB-binding proteins, candidates for the cellular recombinogenic protein, are now isolated and being characterized. We showed the possibility that, in HCV- as well as HBV-associated chronic active liver diseases, the recombinogenic proteins are expressed more abundantly than in the normal liver, and their functions are triggered by the binding to the recombinational hot spot in the chromosomal DNA.

Carcinoma, Hepatocellular↗
PubMed1998

Cell-adhesion-dependent influences on genomic instability and carcinogenesis.

Adhesion-dependent cell signaling is known to be important in carcinogenesis. It is postulated that several types of adhesion molecules act as tumor suppressor genes by enforcing cell-substrate and cell-cell adhesion thereby preventing the migration of cells and their invasion into surrounding tissues. Recent evidence, however, suggests that disruption of adhesion systems can both initiate neoplastic transformation and contribute a rate-limiting step to progression. Adhesion may modulate neoplastic processes by altering pathways that control genomic stability. Analysis of the adhesion-controlled inactivation of the p53 protein and the concomitant relaxation of cell cycle checkpoint control could identify the critical contributions of adhesion-mediated influences to carcinogenesis.

Cell Adhesion↗
PubMed1999

The genomic structure of the DMBT1 gene: evidence for a region with susceptibility to genomic instability.

Increasing evidence has accumulated for an involvement of the inactivation of tumour suppressor genes at chromosome 10q in the carcinogenesis of brain tumours, melanomas, and carcinomas of the lung, the prostate, the pancreas, and the endometrium. The gene DMBT1 (Deleted in Malignant Brain Tumours 1) is located at chromosome 10q25.3-q26.1, within one of the putative intervals for tumour suppressor genes. DMBT1 is a member of the scavenger-receptor cysteine-rich (SRCR) superfamily and displays homozygous deletions or lack of expression in glioblastoma multiforme, medulloblastoma, and in gastrointestinal and lung cancers. Based on these properties, DMBT1 has been proposed to be a candidate tumour suppressor gene. We have determined the genomic sequence of DMBT1 to allow analyses of mutations. The gene has at least 54 exons that span a genomic region of about 80 kb. We have identified a putative exon with coding potential for a transmembrane domain. Our data further suggest that alternative splicing gives rise to isoforms of DMBT1 with a differential utilization of SRCR domains and SRCR interspersed domains. The major part of the gene harbours locus specific repeats. These repeats may point to the DMBT1 locus as a region susceptible to chromosomal instability.

Agglutinins↗
PubMed1997

p53 mutations, methylation and genomic instability in the progression of chronic myeloid leukaemia.

In chronic myeloid leukaemia (CML), as with other tumour types, mutations of the p53 gene are associated with disease progression. Changes in regional methylation of DNA with CML tumour development have also been demonstrated. Methylation is one mechanism by which gene expression is controlled and the CpG sites, which are the targets of DNA methylation, are also the sites of a number of the mutations found in the p53 gene. Cells harbouring mutant p53 have been shown to accumulate further genomic and genetic aberrations and methylation which alters the conformation of DNA is also believed to play a role in genomic stability. There appears to be an interplay between p53 deregulation and changing methylation patterns with the progression of CML. The cause and effect of changes in both of these critical gene regulating, DNA repair and genomic stability factors and their deviation during the progression of CML will be discussed.

Animals↗
PubMed1998

Bloom's and Werner's syndrome genes suppress hyperrecombination in yeast sgs1 mutant: implication for genomic instability in human diseases.

Bloom's syndrome (BS) and Werner's syndrome (WS) are genetic disorders in which an increased rate of chromosomal aberration is detected. The genes responsible for these diseases, BLM and WRN, have been found to be homologs of Escherichia coli recQ and Saccharomyces cerevisiae SGS1 genes. Here we show that yeast Sgs1 helicase acts as a suppressor of illegitimate recombination through homologous recombination and that human BLM and WRN helicases can suppress the increased homologous and illegitimate recombinations in the S. cerevisiae sgs1 mutant. The results imply a role of BLM and WRN helicases to control genomic stability in human cells. Similar to Sgs1 helicase, BLM helicase suppressed the cell growth in the top3 sgs1 mutation background and restored the increased sensitivity of the sgs1 mutant to hydroxyurea, but the WRN helicase did not. We discussed differential roles of BLM and WRN helicases in human cells. BLM- and WRN-bearing yeasts provide new useful models to investigate human BS and WS diseases.

Base Sequence↗