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Results for “Chromosomal Instability”

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PubMed2003

Chromosome instability induced in vitro with mitomycin C in five Seckel syndrome patients.

Seckel syndrome (SS) is an autosomal recessive entity characterized by proportionate pre- and post-natal growth retardation, microcephaly, typical facial appearance with beak-like protrusion, and severe mental retardation. A heterogeneous basis for SS was proposed since around 25% of SS patients have hematological anomalies, suggesting a subgroup of SS with chromosome instability and hematological disorders. Chromosome instability induced by mitomycin C (MMC) has been observed in previous reports. The purpose of this study is to report cytogenetic features in five patients with SS. The patients had low birth weight (mean 1,870 g), short stature (SD = 6.36), microcephaly (OFC, SD = 8.1), typical facial appearance, and multiple articular dislocations. None of them had anemia at the time of examination. In all cases their parents were healthy and non-consanguineous. Lymphocytes of SS patients and a control group (n = 9) matched by age and sex were cultured with and without MMC, and harvested at 72 and 96 hr. Chromosomal aberrations (chromatid and chromosomal gaps and breaks, deletions, fragments, and exchanges) were scored in 100 metaphases per culture. A statistical increase of chromosomal aberrations was observed in 96 hr MMC cultures in all patients (40.2% vs. 2.8%). Sister chromatid exchanges were also performed with no differences between groups. Clinical and cytogenetic findings support the idea that SS may correspond to a chromosome instability syndrome.

Abnormalities, Multiple↗

PubMed2006

Amplification of the major satellite DNA family (FA-SAT) in a cat fibrosarcoma might be related to chromosomal instability.

Most mammalian chromosomes have satellite DNA sequences located at or near the centromeres, organized in arrays of variable size and higher order structure. The implications of these specific repetitive DNA sequences and their organization for centromere function are still quite cloudy. In contrast to most mammalian species, the domestic cat seems to have the major satellite DNA family (FA-SAT) localized primarily at the telomeres and secondarily at the centromeres of the chromosomes. In the present work, we analyzed chromosome preparations from a fibrosarcoma, in comparison with nontumor cells (epithelial tissue) from the same individual, by in situ hybridization of the FA-SAT cat satellite DNA family. This repetitive sequence was found to be amplified in the cat tumor chromosomes analyzed. The amplification of these satellite DNA sequences in the cat chromosomes with variable number and appearance (marker chromosomes) is discussed and might be related to mitotic instability, which could explain the exhibition of complex patterns of chromosome aberrations detected in the fibrosarcoma analyzed.

Animals↗

PubMed1998

Chromosomal instability in the descendants of unirradiated surviving cells after alpha-particle irradiation.

We have demonstrated chromosomal instability in the clonal descendants of hemopoietic stem cells after irradiating murine bone marrow with alpha-particles. However, because cells that are irradiated by alpha-particles are defined by a Poisson distribution of individual particle traversals, there is an inevitable proportion of unirradiated cells in the surviving population. The calculated expected proportions of irradiated and nonirradiated cells indicate that the number of clonogenic cells transmitting chromosomal instability is greater than the number expected to be hit and survive. To investigate further this discrepancy, we studied the effects of interposing a grid between the cells and the alpha-particle source so that the surviving population consists predominantly of untraversed stem cells. Comparison with the same irradiation conditions without the grid reveals that the same level of instability is induced. The data confirm that alpha-particles induce chromosomal instability but instability is demonstrated in the progeny of nonirradiated stem cells and must be due to unexpected interactions between irradiated and nonirradiated cells. This untargeted effect has important implications for mechanistic studies of radiation action and for assessment of radiation risk.

Abnormalities, Radiation-Induced↗

PubMed2003

Phenotype-based identification of mouse chromosome instability mutants.

There is increasing evidence that defects in DNA double-strand-break (DSB) repair can cause chromosome instability, which may result in cancer. To identify novel DSB repair genes in mice, we performed a phenotype-driven mutagenesis screen for chromosome instability mutants using a flow cytometric peripheral blood micronucleus assay. Micronucleus levels were used as a quantitative indicator of chromosome damage in vivo. Among offspring derived from males mutagenized with the germline mutagen N-ethyl-N-nitrosourea (ENU), we identified a recessive mutation conferring elevated levels of spontaneous and radiation- or mitomycin C-induced micronuclei. This mutation, named chaos1 (chromosome aberration occurring spontaneously 1), was genetically mapped to a 1.3-Mb interval on chromosome 16 containing Polq, encoding DNA polymerase theta. We identified a nonconservative mutation in the ENU-derived allele, making it a strong candidate for chaos1. POLQ is homologous to Drosophila MUS308, which is essential for normal DNA interstrand crosslink repair and is unique in that it contains both a helicase and a DNA polymerase domain. While cancer susceptibility of chaos1 mutant mice is still under investigation, these data provide a practical paradigm for using a forward genetic approach to discover new potential cancer susceptibility genes using the surrogate biomarker of chromosome instability as a screen.

Animals↗

PubMed2002

Chromosome instability in malignant astrocytic tumors detected by fluorescence in situ hybridization.

Malignant tumors intrinsically manifest genetic instability, and consequently genetic aberrations successively accumulate in tumor cells as the tumor progresses. However, the relationship of genetic instability and biological behavior still remains to be investigated in malignant tumors. In the present investigation, the relationship between chromosomal instability and patient prognosis was studied in 19 malignant gliomas. Chromosomal instability was estimated by numerical variation in chromosomes 7, 10 and 17 which was measured by fluorescence in situ hybridization (FISH), and DNA ploidy was determined by laser scanning cytometry. The mean number of fractions was significantly higher in cases with DNA aneuploidy than in those with DNA diploidy. The tendency toward higher fractions in glioblastomas existed, although it did not reach statistical significance. Kaplan-Meier survival rate analysis demonstrated significantly lower survival rates in patients with higher fractions of chromosome 7 (>5) than others. Our results suggest that DNA aneuploidy in malignant gliomas reflects an underlying chromosomal instability, and that this instability is associated with clinical behavior.

Adult↗

PubMed2000

Evidence of chromosome instability in chronic pancreatitis.

In the current study we analyzed chromosome instability on peripheral blood lymphocytes cultured from 7 untreated patients with chronic pancreatitis (CP) by assessing telomeric associations (TAS), chromosome aberrations (CA) and sister chromatid exchanges (SCE). Seven healthy individuals were also analyzed. Mean frequencies of TAS were significantly higher in CP patients (X +/- SE: 11.00 +/- 2.37) compared to controls (1.00 +/- 0.30) (p<0.001). Chromosomes preferentially involved in TAS were: 9, 20, 16 and 21, being the most affected arms: 9p, 20q, 16p, 9q and 21q. All these terminal bands were coincident with cancer breakpoints (p<0.03), two of them (40%) were specifically associated to pancreatic carcinoma rearrangements. Three bands (60%) were coincident with oncogene location. The mean frequency of CA was significantly higher in patients (3.88 +/- 0.80) compared to controls (0.63 +/- 0.49) (p<0.001). Chromosomes 1, 2 and 13 were the most damaged. No specifically affected breakpoints were found. SCE analysis showed higher levels in patients (8.33 +/- 0.70) than in controls (6.62 +/- 0.34) (p<0.025), but no differences were observed in cell cycle kinetics. Our results clearly indicate that CP patients exhibit chromosome instability, showing the presence of an unstable genome that could be related to the cancer development observed in this disease.

Aged↗

PubMed1998

Recombination involving interstitial telomere repeat-like sequences promotes chromosomal instability in Chinese hamster cells.

The physical termini of mammalian chromosomes are capped with tandem repeats of the telomere sequence (TTAGGG)n. After fluorescence in situ hybridization with a labeled (TTAGGG)n probe, telomere-repeat-like sequences are seen as discrete bands at distinct intrachromosomal sites in a variety of vertebrate species. There is increasing evidence that these sites may be hot-spots for chromosomal rearrangements, fragility and neoplasia. We have investigated whether the interstitial telomere bands found in hamster chromosomes from a human hamster hybrid cell line are hot-spots for chromosome rearrangements induced by DNA-damaging agents. Our data indicate that the interstitial telomere bands are involved in chromosomal rearrangements observed at the first mitosis after G1 exposure of cells to X-rays or restriction endonucleases at a four- to fivefold higher frequency than expected based on their size. In addition, we have extended these observations to demonstrate for the first time that these interstitial telomere-repeat-like sequences participate in the delayed chromosomal instability observed in the progeny of cells surviving X-ray-exposure at multiple generations after irradiation. In two highly unstable clones showing multiple populations of rearranged chromosomes, interstitial telomere bands were observed at the site of recombination between the human and hamster chromosomes at a five- to sixfold higher frequency than expected. There were also rearrangement and amplification of the interstitial telomere bands within the hamster chromosomes. These rearrangements occur during clonal expansion of cells surviving treatment with DNA-damaging agents and suggest a role for the interstitial telomere band in driving chromosomal instability. We conclude from the observed data that interstitial telomere bands function as recombinational hot-spots that participate in generating the diverse chromosome rearrangements observed both immediately and as a delayed effect of cellular exposure to DNA damaging agents.

Animals↗

PubMed1989

Increased bleomycin-induced chromosome damage in lymphocytes of patients with common variable immunodeficiency indicates an involvement of chromosomal instability in their cancer predisposition.

To study mutagen-induced chromosome instability in cancer disposition, late S and G2 lymphocytes of 15 patients with common variable immunodeficiency and 14 healthy controls were exposed to bleomycin in vitro. The groups did not differ in the frequency of spontaneous chromosome aberrations. In bleomycin-treated samples we found higher numbers of break events per cell and increased frequency of cells with aberrations compared to the control group. A slightly reduced breakage of chromosome group D was noted in patients. These results support the hypothesis that a higher incidence of cancer in patients with genetically determined immunodeficiencies may be explained by an increased mutagen-induced chromosome instability in at least some of them.

Bleomycin↗

PubMed1997

Latent chromosomal instability in cancer patients.

There is increasing evidence that, similar to what is found with other genetic disorders, genomic instability is one of the most general features of cancer. Different forms of manifestation including latent instability have been suggested. To recognize latent chromosomal instability we treated lymphocyte cultures of cancer patients and healthy persons with caffeine, two different doses of bleomycin, and a combination of bleomycin and caffeine. The preliminary results demonstrate that, although the rate of spontaneous chromosomal aberrations is similar in both investigated groups, the lymphocytes of cancer patients display an increased susceptibility to treatment with bleomycin and caffeine. In distinguishing between healthy individuals and those with malignancy, treatment with 30 micrograms/ml bleomycin appears to be most important. Values of chromosomal change above one break per cell, more than 45% cells with chromosomal alterations, and more that two cells with chromosomal rearrangements are suggestive of malignancy. These findings imply that treatment of lymphocyte cultures with bleomycin and caffeine could be a useful assay for monitoring chromosomal instability, and thus detecting a predisposition to malignant disease. In this respect further investigations on a greater amount of material should be performed.

Adult↗

PubMed2002

The structural nature of chromosomal instability in colon cancer cells.

Biological and genetic cell heterogeneity is a landmark of most colorectal cancers and provides a frame for tumor progression as an evolutional process. Classical models have hypothesized that increased genetic instability may contribute to modulating and shaping malignant transformation. This is true for the small subset of colorectal cancers displaying microsatellite instability. For the rest of colorectal tumors, numerical and/or structural chromosomal alterations are the most prominent outcome of genetic disruption. These observations have prompted some investigators to hypothesize about the presence of chromosomal instability in these cells. To characterize chromosomal instability in cancer cells, we have analyzed genetic clonal divergence in three colorectal cancer cell lines considered to be archetypes in cancer research (HCT116, LoVo, and SW480). A dynamic setting was designed to allow the calculation of mutation rates. Comprehensive analyses at the chromosomal level revealed distinctive patterns of genetic divergence. Aneuploid SW480 cells displayed high rates of structural alterations (>100-fold) as compared with near diploid LoVo cells. Numerical alterations also occurred more frequently in SW480 cells but at low rates as compared with rearrangements in the chromosomically unstable SW480 cells. These results strengthen the role of structural instability in the generation of genetic heterogeneity in colorectal cancer.

Chromosome Aberrations↗

PubMed2001

TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines.

Telomere shortening in telomerase-negative somatic cells leads to the activation of the TP53 protein and the elimination of potentially unstable cells. We examined the effect of TP53 gene expression on both telomere metabolism and chromosome stability in immortal, telomerase-positive cell lines. Telomere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell lines that vary in TP53 expression; TK6 cells express wild-type TP53, WTK1 cells overexpress a mutant form of TP53, and NH32 cells express no TP53 protein. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chromosome instability. The shortest telomeres were found in WTK1- and NH32-derived cells, and these cells had 5- to 10-fold higher levels of chromosome instability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found only in WTK1-derived cells. Both telomere length and chromosome instability fluctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telomere lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability.

Cell Line, Transformed↗

PubMed2025

CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution.

Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG, [Formula: see text]). We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Analysis of inference results using CINner across cancer types in The Cancer Genome Atlas ([Formula: see text]) further reveals that the inferred selection parameters reflect the bias between tumor suppressor genes and oncogenes on specific genomic regions. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) in PCAWG uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions (chronic lymphocytic leukemia in PCAWG, [Formula: see text]). Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.

Chromosomal Instability↗

PubMed1990

The effect of retinoids, carotenoids and phenolics on chromosomal instability of bovine papillomavirus DNA-carrying cells.

Antioxidants were found to protect against the genotoxic effects of chemical and physical mutagenic and clastogenic agents. This study focused on the capacity of antioxidants to reduce an intrinsic and persistent chromosome instability. As a model system, strains of C127 cells, which were transformed by bovine papillomavirus (BPV) DNA and which carry BPV DNA varying from 20 to 160 copies, were used. Transformed cells of 10 different strains showed a persistently high incidence of mitotic irregularities detectable at anaphase and telophase (27.3-58.9%), an elevated frequency of cells with micronuclei (6.6-34.7%), and a broad spectrum of nuclear sizes, as measured by image analysis. A 3-day exposure to retinoic acid, retinol, beta-carotene, canthaxanthin, ascorbic acid and ellagic acid greatly reduced the degree of chromosome instability, whereas catechin, eugenol and pyrogallol showed a smaller inhibitory effect, and curcumin had no detectable effect on the frequency of mitotic irregularities. After withdrawal of retinoic acid treatment, the high levels of chromosome instability reappeared. The possibility that the protective effect of the retinoids and carotenoids examined in the model system points to their beneficial administration to human cells with an intrinsic or acquired chromosome instability is discussed.

Antioxidants↗

PubMed2005

STK15 gene overexpression, centrosomal amplification, and chromosomal instability in the absence of STK15 mutations in laryngeal carcinoma.

Centrosomes regulate cell division by forming bipolar mitotic spindles and, thus, play an essential role in the maintenance of chromosomal stability. Centrosomal amplification has been found commonly among tumor cells. Previous studies have suggested that a STK15 (serine/threonine kinase 15) gene can induce centrosomal amplification, chromosomal instability, and cell transformation. To investigate the role of STK15 gene abnormalities in the occurrence of centrosomal amplification and chromosomal instability, a combinatory approach has been taken to investigate the expression level and point mutations of the STK15 and centrosomal/chromosomal aberrations among 72 cases of laryngeal squamous cell carcinoma and a representative Hep-2 cell line. Although no mutation was detected within its exons 6 or 7, overexpression of STK15 has been found in 47 cases (65 percent) as well as in the Hep-2 cell line; for the latter apparent centrosomal amplification also has been noted, with the number of centrosomes within a single cell varying between 1 and 7 and the proportion of cells with amplified centrosomes reaching 11 approximately 23 percent. Karyotype analysis of Hep-2 cell line has suggested common occurrence of chromosomal aberrations, with the number of chromosomes ranging between 43 and 84, modal number between 69 and 74, and structural aberrations, represented by 13 marker chromosomes, including translocations, deletions, and isochromosomes found in various subclones. Our results suggest that in Hep-2 cell line overexpression of STK15 gene may cause centrosomal amplification thereby result in chromosomal instability through abnormal mitosis. Detection of STK15 overexpression in laryngeal carcinoma has led us to propose that the above may be one of the mechanisms underlying laryngeal carcinogenesis.

Aurora Kinase A↗

PubMed1997

Differential induction of chromosomal instability by DNA strand-breaking agents.

To investigate the role of DNA strand breakage as the molecular lesion responsible for initiating genomic instability, five different strand-breaking agents, bleomycin, neocarzinostatin, hydrogen peroxide, restriction endonucleases, and ionizing radiation, were examined for their capacity to induce delayed chromosomal instability. These studies used GM10115 human-hamster hybrid cells, which contain one copy of human chromosome 4 in a background of 20-24 hamster chromosomes. Chromosomal instability was investigated using fluorescence in situ hybridization to visualize chromosomal rearrangements involving the human chromosome. Rearrangements are detected multiple generations after treatment, in clonal populations derived from single progenitor cells surviving treatment of the specified DNA-damaging agents. Clastogenic and cytotoxic activities of all agents were tested by examining chromosome aberration yields in first-division metaphases and by clonogenic survival assays. Analysis of over 250 individual clones representing over 50,000 metaphases demonstrates that when compared at comparable levels of cell kill, ionizing radiation, bleomycin, and neocarzinostatin are equally effective at eliciting delayed genomic instability. These observations document, for the first time, the persistent destabilization of chromosomes following chemical treatment. In contrast, the analysis of nearly 300 clones and 60,000 metaphases, involving treatment with four different restriction endonucleases and/or hydrogen peroxide, did not show any delayed chromosomal instability. These data indicate that DNA strand breakage per se does not necessarily lead to chromosomal instability but that the complexity or quality of DNA strand breaks are important in initiating this phenotype.

Adenine Phosphoribosyltransferase↗

PubMed2002

Increased error-prone non homologous DNA end-joining--a proposed mechanism of chromosomal instability in Bloom's syndrome.

BS is an inherited cancer predisposition disorder caused by inactivation of the RecQ family helicase, BLM. One of the defining features of cells from BS individuals is chromosomal instability, characterized by elevated sister chromatid exchanges (SCEs), as well as chromosomal breaks, deletions, and rearrangements. Although the basis for chromosomal instability is poorly understood, there is evidence that chromosomal abnormalities can arise through an alteration in the efficiency or fidelity of DNA double strand break (DSB) repair. Here, we show that BS cells demonstrate aberrant DSB repair mediated by the non-homologous end-joining (NHEJ) pathway for DNA repair, one of the two main pathways for the repair of DSBs in mammalian cells. Through a comparison of BS cell lines, and a derivative in which the BS phenotype has been reverted by expression of the BLM cDNA, we show that BS cells display aberrant end-joining of DSBs. Importantly, DNA end-joining in BS cells is highly error-prone and frequently results in DNA ligation at distant sites of microhomology, creating large DNA deletions. This aberrant repair is dependent upon the presence of the Ku70/86 heterodimer, a key component in the NHEJ pathway. We propose that aberrant NHEJ is a candidate mechanism for the generation of chromosomal instability in BS.

Antibodies↗

PubMed2000

Dose- and time-response relationships for lethal mutations and chromosomal instability induced by ionizing radiation in an immortalized human keratinocyte cell line.

PURPOSE: To investigate the relationship between two well-established delayed effects of ionizing radiation, experiments were conducted to determine the induction and expression of lethal mutations (delayed reproductive death) and chromosomal instability with respect to dose and time in a human immortalized keratinocyte cell line. METHODS: HPV-G cells were gamma- or alpha-irradiated and maintained in culture for up to 72 population doublings. At intervals, measurements were made of cloning efficiency and the cells examined for apoptosis and cytogenetic aberrations. RESULTS: The descendants of cells surviving 1 or 3 Gy gamma-irradiation, but not 0.5 Gy gamma-irradiation, exhibited a reduced colony-forming efficiency. The reduction persisted at a constant rate of 15-20% clonogenic cell loss per population doubling for up to 72 population doublings. Apoptosis was demonstrated in all colonies in the 1 and 3 Gy groups at 30 and 72 population doublings post-irradiation but not in the 0.5 Gy group. A significant persistent reduction in colony-forming ability (approximately 80%) was demonstrated in the progeny of cells irradiated with 0.5 Gy alpha-particles. After 30 population doublings, the proportion of chromosomally aberrant cells was significantly greater than control values for all doses of both high- and low-LET radiations. The major cytogenetic aberrations (chromatid breaks, chromosome fragments and minutes) were consistent with the transmission of chromosomal instability. The expression of instability declined between 30 and 72 population doublings in the 0.5 Gy and 3 Gy gamma-irradiation groups, but persisted up to 72 population doublings in the 1 Gy group. The expression of chromosomal instability was greater in the descendants of alpha-irradiated cells and showed little evidence of reduction with time. CONCLUSIONS: Unstable aberrations characteristic of radiation-induced chromosomal instability may commonly result in apoptosis and account for a component of the delayed reproductive death/lethal mutation phenotype in HPV-G cells. However, the absence of lethal mutations in the descendants of 0.5 Gy gamma-irradiated cells indicates a low-LET threshold effect for this particular endpoint. Overall, and particularly at low doses, there is no direct correlation between the two endpoints, indicating the absence of a simple relationship between these manifestations of radiation-induced genomic instability.

Alpha Particles↗

PubMed2004

Telomere erosion and chromosomal instability in cells expressing the HPV oncogene 16E6.

Progression to advanced-stage cervical carcinomas is characterized by a recurrent pattern of chromosomal rearrangements. Structural chromosome rearrangements are generated through the fusion of broken chromosome ends. These chromosome breaks may be induced by mutagenic agents such as ionizing radiation, or chromosome ends may be exposed through extensive telomere shortening. The human papilloma virus oncogene 16E6 induces telomerase activity in human keratinocytes, a model system for cervical tumor formation. The present study explores the relationship between 16E6 expression, telomerase activity, and chromosomal instability. We show that the frequency of anaphase bridges is dependent on the level of telomerase activity in 16E6/E7-expressing clones, and is the result of telomere shortening. High frequencies of anaphase bridges, associated with low telomerase activity, correlate with increased chromosome instability. Anaphase bridge formation is also associated with the presence of micronuclei, which are shown to contain unstable chromosomes frequently involved in rearrangements. As anaphase bridges are observed in both high and low telomerase 16E6/E7 clones, but not in hTERT-expressing control clones, expression of 16E6 in these immortalized clones is not sufficient to stabilize shortened telomeres completely. We suggest a model in which HPV-induced tumorigenesis may be dependent on persistent bridge-breakage-fusion cycles that allow for continued genomic rearrangements.

Anaphase↗