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Results for “Chromosomal Instability”

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PubMed2003

[Manifestation of glutathione S-transferase GSTM1 and GSTT1 in female patients with bleomycin-positive chromosome instability].

OBJECTIVES: The purpose of this research is to assess the incidence of gene polymorphisms coding the GSTM1 and GSTT1 enzymes in a population of female patients with chromosome instability. MATERIALS AND METHODS: The PCR method was used to determine the genotype for GSTM1 and GSTT1. The breaks per cell and the percentage of damaged cells were calculated. The separation point used to diagnose chromosome instability in tested females was assumed to be 2.5. RESULTS: In a tested population of 85 females with chromosome instability, the deletion of both the alleles of the GSTT1 gene was observed in 22 females (25% of the group) and deletion of both the alleles of the GSTM1 gene was observed in 42 females (53% of the group). In addition, the incidence of individual genes was calculated for the tested population. The X2 test showed that the differences between the observed and expected values of the tested genes were statistically immaterial, i.e. the likelihood of randomness for these differences exceeded 99%. CONCLUSIONS: No relationship between the manifestation of genotypes for the GSTM1 and GSTT1 glutathione S-transferases and an increased chromosome instability confirmed with the bleomycin test was proven for a population of females with a neoplastic risk.

Adult↗

PubMed2004

Low level chromosome instability in embryonic cells of primary aneuploid mice.

Karyotypic analyses of Down syndrome patients have identified a low level of chromosome mosaicism, suggesting that the primary aneuploid status of the cells promotes further chromosomal segregation errors. Sycp3-null female mice produce aneuploid oocytes, which after fusion with normal haploid sperm, result in offspring with systemic whole chromosome, aneuploid embryo cells. Using the Sycp3-null female as a model, we observe an increase in the number of embryonic cells at E7.0 that exhibit abnormal chromosomal bridges at the anaphas estage of mitosis. This result suggests that global changes in gene expression patterns resulting from primary aneuploidy can affect mitotic chromosome segregation, resulting in a low level of chromosomal instability. The increased level of chromosomal instability could in the absence of mitotic checkpoints, lead to chromosomal mosaicism within the adult organism, as seen in Down syndrome patients.

Aneuploidy↗

PubMed2003

Excessive centrosome abnormalities without ongoing numerical chromosome instability in a Burkitt's lymphoma.

Numerical and structural centrosome abnormalities are detected in various human malignancies and have been implicated in the formation of multipolar mitoses, chromosome missegregation, and chromosomal instability. Despite this association between centrosome abnormalities and cancerous growth, a causative role of centrosome aberrations in generating chromosomal instability and aneuploidy has not been universally established. We report here excessive numerical and structural centrosome abnormalities in a malignant Burkitt's lymphoma harboring the characteristic t(8;14) chromosomal translocation. Using conventional karyotyping and fluorescence in situ hybridization (FISH), we detected no signs of ongoing numerical chromosome instability, although the tumor displayed sporadic multipolar metaphases. These findings demonstrate that centrosome abnormalities are not a universal surrogate marker for chromosomal instability in malignant tumors. Moreover, our results suggest a model in which additional cellular alterations may be required to promote centrosome-related mitotic defects in tumor cells.

Adult↗

PubMed1999

No chromosomal instability in offspring of survivors of childhood malignancy.

Chromosomal instability was examined in 20 apparently healthy children of survivors of childhood malignancy. As compared to controls, no increase of spontaneous or bleomycin-induced aberrations (including gaps, breaks, sister chromatid exchanges, pulverization, and premature centromere divisions) were found in these "index children." The results suggest that the offspring of subjects previously receiving chemotherapy and/or radiotherapy for childhood malignancy are probably at no increased risk of latent chromosomal instability.

Bleomycin↗

PubMed2006

Chromosome instability in a calf with amelia of thoracic limbs.

We report here on a case of a Holstein-Friesian male calf with the congenital total absence of thoracic limbs (amelia). Cytogenetic study showed a high rate of chromosome instability, represented by chromosome or chromatid breaks and gaps in 46% of the analyzed metaphase spreads. Moreover, 12% of the spreads appeared to be polypolid. The number of micronuclei also was significantly higher when compared to control animals. This paper discusses the association between chromosome instability and limb malformation.

Animals↗

PubMed2000

Association of allelic imbalance at locus D13S171 (BRCA2) and p53 alterations with tumor kinetics and chromosomal instability (aneuploidy) in nonsmall cell lung carcinoma.

BACKGROUND: BRCA2 gene, located at chromosome 13q12.3, frequently is altered in familial types of cancer in which a "double-hit" inactivation model seems to occur. In contrast, in sporadic forms of cancer there is frequent absence of a second event (point mutations) suggesting that allelic imbalance at the BRCA2 locus may be associated with a "gene dosage effect" of BRCA2 function. Little is known about BRCA2 allelic alterations in nonsmall cell lung carcinomas (NSCLCs). Furthermore, recent studies suggest that BRCA2 and p53 participate in a common pathway involved in DNA damage repair. In view of this putative link, the authors investigated in a series of 63 NSCLCs: 1) the allelic imbalance (AIm) at the D13S171 (BRCA2) locus, 2) the possible relation with tumor kinetics (proliferation [PI] and apoptotic indices [AI]) and chromosomal instability (aneuploidy) of the carcinomas, and 3) the mutual impact of D13S171 AIm and p53 altered status on the above-mentioned parameters. METHODS: Allelic status of the BRCA2 region was examined in a series of 63 NSCLCs, by using the polymorphic marker D13S171, which is located in the center of it. Most information regarding the status of p53 at the immunohistochemical and genetic levels was obtained from a previous analysis. Tumor kinetic parameters (proliferation and apoptotic indices) were determined using Ki-67 immunohistochemical analysis and Tdt-mediated dUTP nick end labeling assay, respectively. Chromosomal instability (aneuploidy) was assessed by measuring nuclear DNA ploidy with an image analysis system. RESULTS: Allelic imbalance at D13S171(BRCA2) was observed in 70% of the informative cases (H: heterozygous) with a rather high frequency of occurrence (50%) in Stage I disease, suggesting a possible early involvement in the development of NSCLCs. Although no association was found among loss of heterozygosity (LOH) at D13S171, kinetic parameters and ploidy status of the tumors and concurrent alterations in BRCA2 and p53 (BRCA2[LOH]/p53[P]), which was the most frequent profile (37.2%), had the highest growth index (PI/AI mean value ratio) that differed significantly only from the BRCA2(LOH)/p53(N) pattern (P = 0.027). This difference was attributed to the high AI of the BRCA2(LOH)/p53(N) pattern (P < 0.001), whereas PI was similar among all BRCA2/p53 profiles. Also the "full abnormal pattern" was associated with aneuploidy, whereas the BRCA2(LOH)/p53(N) profile was mainly diploid. When these indicators and conventional prognostic ones were examined for effect on patient survival, only stage and lymph node status showed a significant correlation, whereas LOH at D13S171 (BRCA2), p53 abnormalities, proliferative and apoptotic indices, ploidy status, smoking history, and histology and combinations of LOH and p53 abnormalities failed to show significant correlation with survival. CONCLUSIONS: These findings suggest that in BRCA2(LOH) NSCLCs the status of p53 (wild type or mutant) represents a decisive determinant of tumor growth and chromosomal instability. Nevertheless, a possible synergistic effect from loss of D13S171 region with p53 abnormalities cannot be excluded because the BRCA2(LOH)/p53(P) profile compared with the BRCA2(H)/p53(P) one had a higher PI/AI mean value ratio (31.05 vs. 22.97), although it was not statistically significant. However, we cannot exclude the possibility that LOH at D13S171 reflects deletion of other putative tumor suppressor gene(s) in the proximity of BRCA2. In this respect, more studies are needed to understand the involvement of BRCA2 region alterations in nonsmall cell lung carcinogenesis. (c) 2000 American Cancer Society.

Aneuploidy↗

PubMed2002

Chromosome instability as a result of double-strand breaks near telomeres in mouse embryonic stem cells.

Telomeres are essential for protecting the ends of chromosomes and preventing chromosome fusion. Telomere loss has been proposed to play an important role in the chromosomal rearrangements associated with tumorigenesis. To determine the relationship between telomere loss and chromosome instability in mammalian cells, we investigated the events resulting from the introduction of a double-strand break near a telomere with I-SceI endonuclease in mouse embryonic stem cells. The inactivation of a selectable marker gene adjacent to a telomere as a result of the I-SceI-induced double-strand break involved either the addition of a telomere at the site of the break or the formation of inverted repeats and large tandem duplications on the end of the chromosome. Nucleotide sequence analysis demonstrated large deletions and little or no complementarity at the recombination sites involved in the formation of the inverted repeats. The formation of inverted repeats was followed by a period of chromosome instability, characterized by amplification of the subtelomeric region, translocation of chromosomal fragments onto the end of the chromosome, and the formation of dicentric chromosomes. Despite this heterogeneity, the rearranged chromosomes eventually acquired telomeres and were stable in most of the cells in the population at the time of analysis. Our observations are consistent with a model in which broken chromosomes that do not regain a telomere undergo sister chromatid fusion involving nonhomologous end joining. Sister chromatid fusion is followed by chromosome instability resulting from breakage-fusion-bridge cycles involving the sister chromatids and rearrangements with other chromosomes. This process results in highly rearranged chromosomes that eventually become stable through the addition of a telomere onto the broken end. We have observed similar events after spontaneous telomere loss in a human tumor cell line, suggesting that chromosome instability resulting from telomere loss plays a role in chromosomal rearrangements associated with tumor cell progression.

Animals↗

PubMed2002

Centrosome amplification drives chromosomal instability in breast tumor development.

Earlier studies of invasive breast tumors have shown that 60-80% are aneuploid and approximately 80% exhibit amplified centrosomes. In this study, we investigated the relationship of centrosome amplification with aneuploidy, chromosomal instability, p53 mutation, and loss of differentiation in human breast tumors. Twenty invasive breast tumors and seven normal breast tissues were analyzed by fluorescence in situ hybridization with centromeric probes to chromosomes 3, 7, and 17. We analyzed these tumors for both aneuploidy and unstable karyotypes as determined by chromosomal instability. The results were then tested for correlation with three measures of centrosome amplification: centrosome size, centrosome number, and centrosome microtubule nucleation capacity. Centrosome size and centrosome number both showed a positive, significant, linear correlation with aneuploidy and chromosomal instability. Microtubule nucleation capacity showed no such correlation, but did correlate significantly with loss of tissue differentiation. Centrosome amplification was detected in in situ ductal carcinomas, suggesting that centrosome amplification is an early event in these lesions. Centrosome amplification and chromosomal instability occurred independently of p53 mutation, whereas p53 mutation was associated with a significant increase in centrosome microtubule nucleation capacity. Together, these results demonstrate that independent aspects of centrosome amplification correlate with chromosomal instability and loss of tissue differentiation and may be involved in tumor development and progression. These results further suggest that aspects of centrosome amplification may have clinical diagnostic and/or prognostic value and that the centrosome may be a potential target for cancer therapy.

Aneuploidy↗

PubMed1995

Premature centromere division: a possible manifestation of chromosome instability.

Retrospective analysis of "routine" chromosome preparations from 2 patients with Fanconi anemia and 2 others with ataxia-teleangiectasia showed increased chromosome breakage and a tendency to premature centromere division (PCD) with special reference to early separation of the large acrocentric (13-15) chromosomes. The findings suggest that PCD may be a manifestation of chromosome instability related to potential malignancy.

Adolescent↗

PubMed2004

[Recent progress in molecular mechanisms of chromosome instability and their association with carcinogenesis].

The persistent presence of chromosome instability (CIN) has been demonstrated in majority of human cancers, particularly in solid cancers. Recent progress in molecular and cellular biology as well as cytogenetic has shed light on the possible molecular mechanisms and their association with carcinogenesis. Chromosome instability may result from various causes, including defects of mitotic spindle checkpoint, centrosome aberration, failure of cell cycle checkpoint, DNA double strand break, telomeres dysfunction, hypomethylation and so on. The researches broaden new insight in molecular mechanisms of carcinogenesis and provided new ideas in diagnoses, therapy, classification, and prognosis of cancer.

Animals↗

PubMed1999

Inherited and inducible chromosomal instability: a fragile bridge between genome integrity mechanisms and tumourigenesis.

Cancer is a multi-step process evolving as the result of the accumulation of a number of mutational events. The growing body of evidence implicating genetic instability as a key feature of this evolutionary process and the risk of malignancy associated with chromosomal instability syndromes highlight the importance of understanding the mechanisms that cells use to maintain the integrity of their genomes. Classic examples of inherited chromosomal instability with cancer predisposition are Bloom's syndrome, ataxia telangiectasia, and Fanconi anaemia, although the mechanisms involved are far from understood. Selected features of these inherited disorders are reviewed to provide a background to the more recently discovered inducible chromosomal instability, a phenotype in which apparently normal cells that have survived ionizing radiation and certain chemical insults may produce descendants exhibiting a high frequency of de novo chromosome aberrations and gene mutations. The phenotype is induced at frequencies considerably greater than conventional mutation frequencies but little is understood of the underlying mechanism(s). To date, chromosomal instability induced by ionizing radiation has been the most extensively studied phenotype and it is evident that the expression of inducible instability has a strong dependence on the type of radiation exposure, the cell type irradiated, and the genetic 'predisposition' of the irradiated cell.

Animals↗

PubMed2002

[Expression of STK15 gene and chromosomal instability in laryngeal carcinoma].

To assess the relationship between expression of STK15 gene and chromosomal instability in laryngeal squamous cell carcinoma, RNA was extracted from 50 cases of laryngeal squamous cell carcinoma and paired normal tissue and Hep-2 cell line. cDNA was synthesized through reverse transcription, which was amplified by PCR using beta-actin as contrast. The results of electrophoresis were analysed by software to examine the expression level of STK15 gene in laryngeal carcinoma; karyotype analysis of Hep-2 cell line as an example was performed by routine and high-resolution G-banding techniques. In the 50 cases of laryngeal carcinoma, there were 34 cases whose expression of STK15 gene in tumor was higher than paired normal tissue, occupying 68%. The difference between tumor group and contrast group was prominent by statistic analysis. The expression of STK15 gene in Hep-2 cell line was higher than that of beta-actin; Chromosomal instability in Hep-2 cell line was evident: The chromosomal number range from 43 to 84 and the chromosomal model ranged from 69 to 74. The structural abnormality was represented by 13 marker chromosomes. We discovered the overexpression of STK15 gene in laryngeal carcinoma the first time. It may caused chromosomal instability through abnormal centrosome, therefore having some effect during the occurrence and development of laryngeal carcinoma.

Aurora Kinase A↗

PubMed2025

Surprisingly frequent chromosomal instability in cultivated peanut.

This study, the third in a three-part series, investigates whether chromosomal instability persists in cultivated peanut. The allotetraploid peanut (Arachis hypogaea; genome type AABB) originated from the hybridization and polyploidization of A. duranensis (AA) and A. ipaënsis (BB). Our first study established that this was an extremely narrow genetic origin, likely from a single hybridization event. This raised a paradox: how did such narrow genetics give rise to the phenotypic diversity seen in cultivated peanut? The second study addressed this, showing that a single neoallotetraploid spontaneously generates striking diversity, and that homoeologous exchanges-abundant in early generations following polyploidy-are a key mechanism in creating this diversity. In contrast to this early-generation instability, cultivated peanut is generally considered to be genetically stable, presumably due to selection. This third study tests whether residual instability still occurs in modern peanut. From a single plant of the highly selfed 'genome stock' of the cultivar 'Tifrunner', we advanced lineages through seven generations in a pollinator-free greenhouse. Among 233 plants, we identified three new large-scale chromosomal instability events: a large deletion on chromosome B01, associated with reduced pod width and seed weight, and two ABBB compositions involving chromosomes A02/B02 and A05/B05. With these observations in hand, we reinterpreted previously published data from two recombinant inbred populations. Together, these results indicate that at least 1% of pure pedigree A. hypogaea plants exhibit spontaneous large-scale chromosomal changes-a surprising frequency of instability that likely contributes to peanut's long-term adaptability and evolution.

Arachis↗

PubMed1998

The evolution of chromosomal instability in Chinese hamster cells: a changing picture?

PURPOSE: To investigate the kinetics of chromosomal instability induced in clones of Chinese hamster cells following X-irradiation. MATERIALS AND METHODS: X-irradiated clones of GM10115, human-hamster hybrid cells containing a single human chromosome 4 (HC4), have been previously established. These clones were defined as unstable if they contained > or = three subpopulations of cells with unique rearrangements of HC4 as detected by FISH. Stable and unstable clones were analysed by FISH and Giemsa staining at various times post-irradiation. RESULTS: While most of the stable clones continued to show chromosomal stability of HC4 over time, one became marginally unstable at approximately 45 population doublings post-irradiation. Clones exhibiting chromosomal instability had one of several fates. Many of the unstable clones were showed similar levels of instability over time. However, one unstable clone became stable with time in culture, while another became even more unstable over time. Cytogenetic analyses of all clones after Giemsa staining indicated that in some clones the hamster chromosomes were rearranged independent of HC4, demonstrating increased frequencies of chromatid breaks and dicentric chromosomes. The majority of the unstable clones also had higher yields of chromatid gaps. CONCLUSIONS: These data demonstrate the dynamic nature of chromosomal instability as measured by two different cytogenetic assays.

Animals↗

PubMed2003

Inhibition of histone deacetylase activity increases chromosomal instability by the aberrant regulation of mitotic checkpoint activation.

Histone modification through acetylation and deacetylation is a key process in transcription, DNA replication, and chromosome segregation. During mitosis, histones are highly acetylated and chromatin is condensed. Here, we investigate the mechanistic involvement of histone deacetylase (HDAC) activity in the regulation of mitotic checkpoint activation. Inhibition of HDAC activity was found to cause the improper kinetochore localization of the mitotic checkpoint proteins, and to prolong mitotic arrest, and thus to lead to chromosomal instability due to aberrant exit from the mitotic cell cycle arrest. In addition, treatment with HDAC inhibitor attenuated the activations of p38 and ERK kinases, and increased the expression levels of cIAP-1, suggesting that the observed increased adaptation and chromosomal instability induced by inhibiting HDAC activity might be directly connected with the activations of cell survival and/or antiapoptotic signals. Moreover, the treatment of cells with mitotic defects with HDAC inhibitor increased their susceptibility to chromosomal instability. These results support the notion that HDAC activity plays an important role in the regulation of mitotic checkpoint activation, and thus the aberrant control of HDAC activity contributes to chromosomal instability.

Acetylation↗

PubMed2006

[Chromosome instability syndromes].

Defects of DNA repair underlie genetic syndromes. Chromosomal aberrations and mutations might cause specific inborn defects. There are several syndromes with characteristic clinical features, which appear to be caused by chromosome instability which is a consequence of DNA repair defects. This article describe syndromes where hereditary mutations are the reason of chromosomal instability and cause serious clinical results: ataxia-telangiectasia, Nijmegen breakage syndrome, Bloom syndrome, Fanconi's anemia, ICF syndrome, Roberts syndrome, dominantly inherited--PCD, Werner syndrome, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy (TTD) and Rothmund-Thomson syndrome (RTS).

DNA Repair-Deficiency Disorders↗

PubMed2005

Centrosome amplification, chromosome instability and cancer development.

During mitosis, two centrosomes form spindle poles and direct the formation of bipolar mitotic spindles, which is an essential event for accurate chromosome segregation into daughter cells. The presence of more than two centrosomes (centrosome amplification), severely disturbs mitotic process and cytokinesis via formation of more than two spindle poles, resulting in an increased frequency of chromosome segregation errors (chromosome instability). Destabilization of chromosomes by centrosome amplification aids acquisition of further malignant phenotypes, hence promoting tumor progression. Centrosome amplification occurs frequently in almost all types of cancer, and is considered as the major contributing factor for chromosome instability in cancer cells. Upon cytokinesis, each daughter cell receives one centrosome, and thus centrosome must duplicate once, and only once, before the next mitosis. If centrosomes duplicate more than once within a single cell cycle, centrosome amplification occurs, which is frequently seen in cells harboring mutations in some tumor suppressor proteins such as p53 and BRCA1. The recent studies have provided critical information for understanding how loss of these proteins allows multiple rounds of centrosome duplication. In this review, how centrosome amplification destabilizes chromosomes, how loss of certain tumor suppressor proteins leads to centrosome amplification, and the role of centrosome amplification in cancer development will be discussed.

Cell Cycle↗

PubMed1989

Chromosomal instability in an oxygen-tolerant variant of Chinese hamster ovary cells.

Background levels of chromosomal aberrations and sister-chromatid exchanges (SCEs) were determined in CHO-99 cells, an oxygen-tolerant variant substrain of Chinese hamster ovary (CHO-20) cells capable of stable proliferation under an atmosphere of 99% O2/1% CO2, a level of hyperoxia at which cultured mammalian cells normally cannot survive. The mean chromosomal aberration frequency in CHO-99 cells was as high as 1 aberration per cell (mainly chromatid and chromosome gaps and breaks) versus 0.05 aberration/cell in CHO-20 cells, while the SCE frequency was 1.7- to 2.1-fold increased. While most aberrations were apparently distributed at random over the chromosomes, up to 31% of the aberrations appeared to be involved in site-specific fragility at a homologous site in chromosomes Z3 and Z4. Immediately upon shifting CHO-99 cells to air-equilibrated conditions their SCE frequency decreased to the control level, whereas the aberration rate persisted at a still elevated level of 0.16-0.31 aberration per cell, even after a culture period of 14 weeks under normoxia. This indicates that at least part of the chromosomal instability is a constitutional property of the variant cells, i.e., not directly dependent upon hyperoxic stress. In CHO-99 X CHO-20 hybrids the occurrence of chromatid-type aberrations and fragile site but not that of chromosome-type aberrations was suppressed under normoxic conditions, suggesting that chromatid-type aberrations and fragile site expression on the one hand and chromosome-type aberrations on the other hand are mediated by different constitutional defects in CHO-99 cells. No gross alterations in (deoxy)ribonucleoside triphosphate pools were detected in CHO-99 cells that could be held responsible for their chromosomal instability. In addition, no increased level of DNA damage was detected by the technique of alkaline elution. The excessive chromosomal instability in CHO-99 cells, as observed under hyperoxic conditions, may originate from reactive intermediates giving rise to DNA double-strand breaks and/or a type of DNA lesion that is resistant to the conditions of the alkaline elution technique. However, alternative mechanisms based upon reactive species interfering with DNA replication/repair processes cannot be excluded.

Animals↗