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Results for “Chromosomal Instability”

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PubMed1995

Delayed chromosomal instability in human T-lymphocyte clones exposed to ionizing radiation.

Recent studies have demonstrated that cells which survive alpha-particle and X-ray exposure may show chromosomal instability, i.e. they continue to develop chromosomal aberrations at an increased frequency for many division cycles after the exposure. To characterize this delayed response, we carried out repeated karyotype analyses of X-irradiated T-lymphocytes during clonal expansion in vitro. Human peripheral blood lymphocytes were obtained from a healthy donor and exposed to 3-Gy X-irradiation. Cell survival, estimated by a cell cloning assay, was 5%. Non-irradiated, control cells were studied in parallel. Monoclonal cell lines were established using the T-cell cloning procedure. G-band karyotype analyses were carried out at several intervals during expansion of the clones for up to 2 months. The irradiated clones did not differ from the control clones with regard to growth rate or cytometric DNA profile. Non-irradiated cell clones showed a normal karyotype, with < 10% of sporadic, non-clonal chromosome and chromatid breaks. In the irradiated clones, the karyotypes showed different (sub)clonal chromosome rearrangements, which developed successively during the cultivation time. In addition to these karyotypic abnormalities, > 20% of the cells in these clones had sporadic, non-clonal chromosome aberrations, and there was a tendency of increasing frequency of such aberrations by length of cultivation. Thus, two types of radiation-induced chromosomal instability were observed; (sub)clonal karyotypic abnormalities and sporadic, non-clonal chromosome aberrations. The frequency and kinetics by which these alterations occur in the progeny of X-irradiated T-cells suggest that they arise through different pathways, and argue against their causation by mutation or persistent DNA damage.

Cell Division↗

PubMed2003

Oxidative stress contributes to arsenic-induced telomere attrition, chromosome instability, and apoptosis.

The environmental contaminant arsenic causes cancer, developmental retardation, and other degenerative diseases and, thus, is a serious health concern worldwide. Paradoxically, arsenic also may serve as an anti-tumor therapy, although the mechanisms of its antineoplastic effects remain unclear. Arsenic exerts its toxicity in part by generating reactive oxygen species. We show that arsenic-induced oxidative stress promotes telomere attrition, chromosome end-to-end fusions, and apoptotic cell death. An antioxidant, N-acetylcysteine, effectively prevents arsenic-induced oxidative stress, telomere erosion, chromosome instability, and apoptosis, suggesting that increasing the intracellular antioxidant level may have preventive or therapeutic effects in arsenic-induced chromosome instability and genotoxicity. Embryos with shortened telomeres from late generation telomerase-deficient mice exhibit increased sensitivity to arsenic-induced oxidative damage, suggesting that telomere attrition mediates arsenic-induced apoptosis. Unexpectedly, arsenite did not cause chromosome end-to-end fusions in telomerase RNA knockout mouse embryos despite progressively damaged telomeres and disrupting embryo viability. Together, these findings may explain why arsenic can initiate oxidative stress and telomere erosion, leading to apoptosis and anti-tumor therapy on the one hand and chromosome instability and carcinogenesis on the other.

Acetylcysteine↗

PubMed1985

Evidence for chromosome instability in vivo in Bloom syndrome: increased numbers of micronuclei in exfoliated cells.

The incidence of exfoliated epithelial cells containing micronuclei was determined in two small human populations, one homozygous and the other heterozygous for the Bloom syndrome gene (bl). The objectives of the study were two: to learn whether the chromosome instability featured so prominently by Bloom syndrome (BS) cells proliferating in vitro also occurs in vivo, and as part of a broad survey of various cancer-prone populations, to determine whether estimating micronucleus frequencies in exfoliated cell samples might be useful for identifying individuals with genetically determined chromosome instability. Eight individuals homozygous (bl/bl) for the BS gene, i.e., persons with the clinical syndrome, were examined, along with 11 obligate heterozygotes (bl/+), parents of affected persons. Exfoliated cells were obtained from two sites, the oral cavity and the urinary tract. Striking and statistically highly significant elevations in the frequencies of cells with micronuclei were observed in cells from both sites in bl/bl individuals compared to that in bl/+ (P less than 0.001) and in a control population, indicating that chromosome instability occurs in vivo in BS. In contrast, micronucleus frequencies at either site did not differ significantly between bl/+ individuals and the control population. This survey, in combination with similar earlier ones of populations predisposed to cancer not on a genetic basis but because of exposure to some environmental carcinogen, suggests that the exfoliated cell micronucleus test identifies individuals whose somatic genetic material has, for either genetic or environmental reasons, been damaged in a way that produces chromosome breakage and rearrangement.

Adult↗

PubMed2003

Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/ATLD1) mice.

In this study, mice expressing one of the two Mre11 alleles inherited in the human ataxia-telangiectasia like disorder (A-TLD) were derived. The mutation had a profound maternal effect on embryonic viability, revealing an acute requirement for Mre11 complex function in early embryogenesis. Mre11(ATLD1/ATLD1) mice exhibited several indices of impaired ATM function. The mice also exhibited pronounced chromosomal instability. Despite this phenotypic spectrum, the animals were not prone to malignancy. These data indicate that defective cell cycle checkpoints and chromosomal instability are insufficient to significantly enhance the initiation of tumorigenesis. In contrast, the latency of malignancy in p53(+/-) mice was dramatically reduced. We propose that in Mre11(ATLD1/ATLD1) mice, genome instability and cell cycle checkpoint defects reduce viability in early embryos and in proliferating cells, while promoting malignancy in the context of an initiating lesion.

Animals↗

PubMed1994

Chromosome instability in lymphocytes from patients with celiac disease.

Cytogenetic studies were performed in celiac disease (CD) patients to determine if the presence of chromosome instability is related to the predisposition to cancer. Chromosome aberrations (CA) and sister chromatid exchange (SCE) frequencies in peripheral blood lymphocyte cultures from untreated CD patients and healthy controls were analyzed. Patients showed aberrations in 23% of cells, while only 3% were detected in the control group (p < 0.0001). The mean frequencies of gaps, breaks and total CA were found to be higher in CD patients compared to controls (p < 0.0001). Breakpoint distribution was nonrandom among chromosomes from celiac patients (p = 0.01), but not among controls (p = 0.04). The frequency of SCE/cell showed a mean value of 6.9 +/- 0.6 in CD patients and 7.3 +/- 0.2 in controls. No statistical differences were found. Breakpoints involved in CD patients presented a strong coincidence with the location of fragile sites (78.6%) and sites of cancer chromosome rearrangements (57.1%), most of them (75%) associated with malignant non-Hodgkin lymphomas. These results suggest that CD is a condition with increased chromosome instability characterized by a high level of CA and normal SCE frequencies, probably related to the increased incidence of cancer.

Adolescent↗

PubMed2001

DNA amplification and chromosomal translocations are accompanied by chromosomal instability: analysis of seven human colon cancer cell lines by comparative genomic hybridization and spectral karyotyping.

Genetic instability in human cancers is classified as chromosomal instability (CIN) or microsatellite instability (MIN). DNA amplification and translocations are observed frequently in various cancers. We used comparative genomic hybridization (CGH) and spectral karyotyping (SKY) to study seven human colon cancer cell lines and investigate the relations among genetic instability, DNA amplification, and chromosomal translocations. DNA amplification was found in five cell lines (COLO320DM, COLO201, WiDr, CoCM-1, and CACO-2), and all were aneuploid. In these five cell lines, segments of chromosomes were translocated to other chromosomes. In contrast, cell lines with MIN, DLD-1, and LoVo did not show DNA amplification. The LoVo cells with MIN were considered near diploid and contained translocations. These findings suggest that DNA amplification and chromosomal translocations are accompanied by CIN.

Colonic Neoplasms↗

PubMed2026

A system-level metastable model of cancer evolution: integrating replication stress, cell cycle deregulation and chromosomal instability.

INTRODUCTION: Cancer cell proliferation occurs within the context of persistent genomic instability. In this review, we propose the RS-CCD-CIN axis as a systems-level framework in which replication stress (RS), cell cycle deregulation (CCD) and chromosomal instability (CIN) form an interdependent triad that shapes tumour evolution. This axis represents a constrained metastable state in which genomic instability is tolerated and buffered. The objective of this review is to synthesize the current understanding of how the RS-CCD-CIN axis contributes to tumour heterogeneity, adaptability and therapy response. DISCUSSION: Evidence indicates that RS, CCD and CIN operate as a dynamic, interconnected network rather than as independent processes. Replication stress induces DNA damage and mutagenesis, while partial checkpoint disruption permits cells with unresolved lesions to proliferate. Chromosomal instability generates both structural and numerical alterations, contributing to intratumoural heterogeneity. Together, these processes facilitate adaptation to environmental and therapeutic pressures. Extrachromosomal DNA, micronuclei formation and cytosolic DNA signalling, including the cGAS-STING pathway, connect genomic instability to adaptive responses and immune modulation. Single-cell and spatial profiling reveal temporal and spatial variability in RS, CCD and CIN states, highlighting the limitations of static biomarkers. Therapeutically, targeting individual components often yields limited durability, whereas approaches that simultaneously perturb multiple aspects of the RS-CCD-CIN axis may improve clinical outcomes. CONCLUSIONS: This review highlights the RS-CCD-CIN axis as a fragile and metastable architecture that supports cancer evolution, while also being susceptible to collapse. A deeper understanding of this interconnected framework may inform the development of therapeutic strategies and enhance the management of resistance.

Humans↗

PubMed1997

Induction of chromosomal instability in human mammary cells by neutrons and gamma rays.

There is now substantial evidence that ionizing radiations can induce genomic instability in the form of chromosomal aberrations that appear several cell generations after irradiation. However, questions remain concerning the influence of radiation quality on this phenomenon. In this study, progeny of either gamma- or neutron-irradiated human epithelial MCF-10A cells were examined for chromosomal aberrations between 5 and 40 population doublings postirradiation. Exposure to either type of radiation resulted in an increase in chromatid-type gaps and breaks several doublings after the irradiation; no such effect was observed for chromosome-type aberrations. Neutron-irradiated cells showed consistently elevated frequencies of aberrations compared to nonirradiated controls at all times examined. Aberration frequencies for gamma-irradiated cells were not significantly different from controls until 20 to 35 population doublings postirradiation, where they increased 2-fold above background before returning to near control levels. To our knowledge these data represent the first evidence of chromosomal instability caused by neutron exposure. Results show that while either gamma rays or neutrons are capable of inducing similar types of delayed aberrations, the time course of their appearance can differ markedly.

Breast Neoplasms↗

PubMed2003

Chromosome instability and nibrin protein variants in NBS heterozygotes.

The frequency of spontaneous chromosome abnormalities in peripheral blood lymphocytes and the X-ray G2 sensitivity in lymphoblastoid cell lines (LCL) have been evaluated in heterozygous subjects from three unrelated Nijmegen Breakage Syndrome (NBS) families, characterised by different mutations in the NBS1 gene. In all the 13 NBS heterozygotes analysed, we found spontaneous chromosome instability consisting in chromosome and chromatid breakages and rearrangements, while radiosensitivity was similar to that of control LCLs in seven out of eight tested NBS heterozygotes. The densitometric analysis of nibrin by immunoblotting indicated only a slight reduction in some of the LCLs from NBS carriers, whereas the immunoprecipitation assay appears a more reliable tool to detect NBS carriers. By means of immunoprecipitation, we investigated two homozygous and four heterozygous subjects. In the cells of the NBS patient 668, with the mutation 900del25, an alternative form of nibrin with a molecular weight of approximately 55 kDa has been detected. This variant protein, together with the normal p95, was also found in the LCL 34 established from a carrier of the same family. Signals of nibrin with a molecular weight lower than 95 kDa, but higher than that observed in LCLs 668 and 34, were detected also in three carriers from the family with mutation 835del4.

Adolescent↗

PubMed2004

Analysis of chromosomal instability in focal cortical dysplasia of Taylor's balloon cell type.

Focal cortical dysplasias (FCD) represent a frequent finding in patients with chronic intractable epilepsy. Neuropathological hallmarks include localized dyslamination of the neocortex and neuronal heterotopias in white matter. Balloon cells, similar to those occurring in cortical tubers of patients with tuberous sclerosis (TSC) are observed in numerous patients. These lesions were classified as FCD type IIb (FCD IIb). Recent findings indicate an accumulation of TSC1 polymorphisms as well as loss of heterozygosity (LOH) and/or microsatellite instability (MSI) at the TSC1 locus on chromosome 9q in FCD IIb. Here, we tested the hypothesis of whether chromosomal instability constitutes a genome-wide phenomenon in this patient cohort. Seven microsatellite markers based on a reference panel recommended by the international workshop on microsatellite instability were analyzed in 14 surgical FCD IIb specimens. DNA from single laser-microdissected cells, i.e., balloon cells versus control neurons obtained from adjacent cortex was harvested for PCR amplification and subsequent fluorescent fragment length gel electrophoresis. Our analysis revealed only rare instances of LOH and MSI at genomic loci on 2p and 17q, whereas no alterations were found at informative markers on chromosomes 1p, 5q and 18q. In addition, no loss of repair protein expression (MSH2 or MLH1) has been identified in balloon cell nuclei of FCD IIb specimens. The present data suggest solitary LOH and MSI events at genomic localizations others than the TSC1 locus to occur in FCD IIb. Our findings lend further support to the hypothesis that the molecular pathogenesis of FCD IIb is associated with TSC1.

Chromosomal Instability↗

PubMed1994

Chromosome instability in lymphocytes from patients affected by or genetically predisposed to colorectal cancer.

To determine whether there are chromosomal clues to inherited forms of colorectal cancer, we studied chromosome instability in lymphocytes cultured from persons with sporadic colorectal cancer before treatment and from persons with a genetic predisposition to colorectal cancer due to adenomatous polyposis coli, Peutz-Jeghers syndrome, or juvenile polyposis. Spontaneous aberrations of chromosome number and structure were scored and compared to control studies by the same methods. Sex chromosome aneuploidy was found increased in patients. Autosomal aneuploidy was not increased. Chromosome breakage was elevated in young persons genetically predisposed to colorectal cancer compared to young patients with sporadic colorectal cancer. Chromosome rearrangements, other than those of chromosomes 7 and/or 14, rose with age, particularly in patients. Despite considerable interindividual variations, it would seem that increased chromosome breakage and rearrangement in addition to sex chromosome aneuploidy may be signs of chromosome instability in the predisposition to colorectal cancer.

Adenomatous Polyposis Coli↗

PubMed2004

Centrosome amplification and the origin of chromosomal instability in breast cancer.

The development and progression of aggressive breast cancer is characterized by genomic instability leading to multiple genetic defects, phenotypic diversity, chemoresistance, and poor outcome. Centrosome abnormalities have been implicated in the origin of chromosomal instability through the development of multipolar mitotic spindles. Breast tumor centrosomes display characteristic structural abnormalities, termed centrosome amplification , including: increase in centrosome number and volume, accumulation of excess pericentriolar material, supernumerary centrioles, and inappropriate phosphorylation of centrosome proteins. In addition, breast tumor centrosomes also show functional abnormalities characterized by inappropriate centrosome duplication during the cell cycle and nucleation of unusually large microtubule arrays. These observations have important implications for understanding the mechanisms underlying genomic instability and loss of cell polarity in cancer. This review focuses on the coordination of the centrosome, DNA, and cell cycles in normal cells and their deregulation resulting in centrosome amplification and chromosomal instability in the development and progression of breast cancer.

Aneuploidy↗

PubMed1997

Chromosomal instability in a woman with infertility and two unaffected brothers: a new familial chromosomal breakage syndrome?

Repeated chromosomal analysis of peripheral blood lymphocytes and skin fibroblasts from a woman referred for amenorrhoea, streak gonads, hyperthyroidism, adiposity and elevated alpha-fetoprotein levels but no other manifestations of known chromosomal breakage syndromes demonstrated an increased spontaneous chromosomal breakage rate (ISCBR). Chromatid and chromosomal breaks were more numerous than sporadic rearrangements and dicentric chromosomes. Exposure of the cells to mitomycin C, diepoxybutane, X-rays or UV irradiation induced an increase in chromosomal and chromatid abnormalities over that in controls. A micronucleus assay demonstrated an increase in the incidence of formation of micronuclei and the population doubling time of the fibroblasts of the proposita was delayed. Chromosomal analysis was performed on lymphocytes of the parents and of five sibs of the proposita. Two brothers had chromosomal abnormalities identical to those of the patient and elevated alpha-fetoprotein levels, however, without any clinical abnormalities. The parents were affected by only a moderate ISCBR whereas two brothers and one sister were chromosomally normal. The clinical, chromosomal and biochemical findings in this family represent a novel chromosomal instability syndrome.

Adult↗

PubMed1988

Incontinentia pigmenti, a chromosomal instability syndrome, is associated with childhood malignancy.

Incontinentia pigmenti (IP) is a rare hereditary disorder that has recently been classified as a chromosomal instability syndrome. As in Fanconi anemia and ataxia telangiectasia, spontaneous and inducible chromosomal aberrations primarily of the chromatid type are increased in patients with IP. Both Fanconi anemia and ataxia telangiectasia are genetic diseases that predispose to cancer. A case report of an infant with IP and malignancy (rhabdoid tumor of the kidney) is presented, and five previously reported cases of this association are reviewed. The malignancies in all of these cases occurred before age three, whereas malignancy associated with Fanconi anemia and ataxia telangiectasia tends to appear in late childhood or in adulthood. The chromosomal instability seen with IP may increase the risk for malignancy in young children.

Female↗

PubMed1986

In vivo chromosomal instability in ataxia-telangiectasia homozygotes and heterozygotes.

The exfoliated cell micronucleus test was used to monitor in vivo chromosomal instability in a population comprised of five ataxia-telangiectasia (A-T) homozygotes and seven obligate heterozygotes (parents of A-T patients). This assay was previously validated as a procedure for quantifying non-invasively carcinogen-induced chromosomal aberrations occurring in vivo in epithelial tissues of both the oral cavity and the urinary bladder. The procedure involved taking air-dried smears of three sites in the oral cavity of each examined individual. Desquamated urinary bladder cells were collected by centrifugation of freshly voided urine samples. Frequencies of exfoliated cells in these preparations were determined and compared with control values (individuals with no genetic chromosomal instability and no known carcinogen exposure) for these sites. Exfoliated cell micronucleus (MEC) frequencies were elevated 5- to 14-fold in samples from the A-T homozygotes. This elevation in MEC frequency occurred for both the oral cavity and urinary bladder. Five out of the seven obligate A-T heterozygotes had an elevated MEC frequency in samples from the oral cavity. In addition, all examined urine samples from A-T heterozygotes contained an elevated percentage of micronucleated cells. These data suggest that this assay is suitable for in vivo monitoring of groups of individuals in which genetically produced chromosomal damage occurs. The possibility of A-T heterozygote detection with this simple procedure is of particular significance, since such individuals are believed to comprise up to 1% of the general population, and have been identified as being at elevated risk for cancer.

Ataxia Telangiectasia↗

PubMedDate not supplied

Induction of chromosomal instability by chronic oxidative stress.

Earlier studies using GM10115 cells analyzed the capability of different DNA-damaging agents to induce genomic instability and found that acute oxidative stress was relatively inefficient at eliciting a persistent destabilization of chromosomes. To determine whether this situation would change under chronic exposure conditions, the human-hamster hybrid line GM10115 was cultured under conditions of oxidative stress. Chronic treatments consisted of 1-hour incubations using a range of hydrogen peroxide (25-200 microM) or glucose oxidase (GO; 5-50 mU/ml) concentrations that were administered once daily over 10 to 30 consecutive days. The toxicity of chronic treatments was modest (- one log kill) and consistent with the low yield of first division aberrations (<5%). However, analysis of over 180 clones and 36,000 metaphases indicated that chronic oxidative stress led to a high incidence of chromosomal instability. Treatment of cells with 100 and 200 microM hydrogen peroxide or 50 mU/ml GO was found to elicit chromosomal instability in 11%, 22%, and 19% of the clones analyzed, respectively. In contrast, control clones isolated after mock treatment did not show signs of chromosomal destabilization. These data suggest that chronic oxidative stress constitutes a biochemical mechanism capable of disrupting the genomic integrity of cells.

Animals↗

PubMed2004

Chromosomal instability, aneuploidy, and gene mutations in human sporadic colorectal adenomas.

Whether in vivo specific gene mutations lead to chromosomal instability (CIN) and aneuploidy or viceversa is so far not proven. We hypothesized that aneuploidy among human sporadic colorectal adenomas and KRAS2 and APC mutations were not independent. Additionally, we investigated if 1p34-36 deletions by dual target FISH were associated with aneuploidy. Among 116 adenomas, 29 were DNA aneuploid by flow cytometry (25%) and 29 were KRAS2 mutated (25%). KRAS2 mutations were associated with aneuploidy (P=0.02). However, while G-C and G-T transversions were strongly associated with DNA aneuploidy (P=0.007), G-A transitions were not. Within a second series of 61 adenomas, we found, instead, that APC mutational status and aneuploidy by flow cytometry were not associated. However, a statistically significant association was found with specific APC mutations, i.e., occurring in the mutation cluster region (MCR, codons 1200-1500) or downstream (P=0.016). Finally, the correlation of 1p34-36 deletions with flow cytometric and FISH detected aneuploidy was also significant (P=0.01). Specific KRAS2 and APC mutations and loss of genes in the 1p34-36 region appear associated with aneuploidy suggesting that these events are not independent and may cooperate in inducing human sporadic colorectal adenomas. A cause effect relationship between gene mutations and aneuploidy remains, however, to be demonstrated.

Adenoma↗

PubMedDate not supplied

[The number of aberrations in aberrant cells as a parameter of chromosomal instability. 1. Characterization of dose dependency].

Analysis of chromosome instability (CI) is of great importance in view of pollution of the environment by genotoxic factors. Frequency of aberrant cells, spectrum of chromosome aberrations, damages of aberrant cell and distribution of aberrations in the cells are the most conventional parameters of CI. We have carried out the comparative analysis of the frequency of aberrant cells and the dynamics of aberrant cell damages induced by different mutagenic factors (alpha-irradiation from 241Am, gamma-irradiation from 60Co and tioTEPA) in Allium-test. This comparative analysis denotes that the studied parameters have different dynamics characterizing different mechanisms of CI in Allium cepa L.

Allium↗