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Results for “Chromosomal Instability”

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PubMed2001

[Chromosome instability in women with genital organs carcinoma].

OBJECTIVES: The aim of the current work was the assessment of the mutagen susceptibility of chromosomes of patients with carcinomas in comparison to healthy volunteers. It was interesting whether the bleomycin assay can be useful for searching for more susceptible to cancer disease individuals. MATERIALS AND METHODS: There were 4 groups of patients analysed: controls and three test groups (patients with uterine cervix carcinoma, endometrium carcinoma and ovarian carcinoma). In total 108 female patients were examined by use of bleomycin assay. Lymphocytes were cultured in vitro and treated with bleomycin. The b/c (breaks per cell) index was evaluated by use of light microscopy. RESULTS: Statistically significant increased test values were found in patients with uterine cervix carcinoma, endometrium carcinoma and ovarian carcinoma. CONCLUSIONS: The assessment of chromosome instability could be a useful prognostic test in the diagnosis of carcinoma of female genital organs. The bleomycin assay is useful for searching subpopulations with higher chromosome instability and more susceptible to cancer disease.

Adult↗

PubMed2005

Saccharomyces cerevisiae as a model system to define the chromosomal instability phenotype.

Translocations, deletions, and chromosome fusions are frequent events seen in cancers with genome instability. Here we analyzed 358 genome rearrangements generated in Saccharomyces cerevisiae selected by the loss of the nonessential terminal segment of chromosome V. The rearrangements appeared to be generated by both nonhomologous end joining and homologous recombination and targeted all chromosomes. Fifteen percent of the rearrangements occurred independently more than once. High levels of specific classes of rearrangements were isolated from strains with specific mutations: translocations to Ty elements were increased in telomerase-defective mutants, potential dicentric translocations and dicentric isochromosomes were associated with cell cycle checkpoint defects, chromosome fusions were frequent in strains with both telomerase and cell cycle checkpoint defects, and translocations to homolog genes were seen in strains with defects allowing homoeologous recombination. An analysis of human cancer-associated rearrangements revealed parallels to the effects that strain genotypes have on classes of rearrangement in S. cerevisiae.

Chromosomal Instability↗

PubMed2005

Identification of high frequency of Y chromosome deletions in patients with sex chromosome mosaicism and correlation with the clinical phenotype and Y-chromosome instability.

A mosaic karyotype consisting of a 45,X cell line and a second cell line containing a normal or an abnormal Y chromosome is relatively common and is associated with a wide spectrum of clinical phenotypes. The aim of this study was to investigate patients with such a mosaic karyotype for Y chromosome material loss and then study the possible association of the absence of these regions with the phenotype, diagnosis, and Y-chromosome instability. We studied 17 clinically well-characterized mosaic patients whose karyotype consisted of a 45,X cell line and a second cell line containing a normal or an abnormal Y chromosome. The presence of the Y chromosome centromere was verified by fluorescence in situ hybridization (FISH) and was then characterized by 44 Y-chromosome specific-sequence tagged site (STS) markers. This study identifies a high frequency of Yq chromosome deletions (47%). The deletions extend from interval 5 to 7 sharing a common deleted interval (6F), which overlaps with the azoospermia factor region (AZF) region. This study finds no association between Y-chromosome loci hosting genes other than SRY, and the phenotypic sex, the diagnosis, and the phenotype of the patients. Furthermore, this study shows a possible association of these deletions with Y-chromosome instability.

Cell Line↗

PubMed2002

Chromosomal instability and radiosensitivity in myelodysplastic syndrome cells.

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells. To investigate whether chromosomal instability and/or DNA repair defects are involved in the development of MDS, we measured the micronucleus (MN) frequency in peripheral blood lymphocytes exposed to various doses of X-rays, using a cytokinesis-block micronucleus assay. The spontaneous MN frequencies in RAEB and RAEB-T patients were significantly higher than those in normal individuals (P = 0.0224, P = 0.008, respectively). Also, the X-ray-induced MN frequencies in RA/RARS, RAEB, and RAEB-T patients were significantly higher than those in normal individuals (P = 0.007, P = 0.003, P = 0.003, respectively, at 2 Gy). In order to elucidate the cause of unusual radiosensitivity, we measured the expression levels of nucleotide excision repair (NER) genes in peripheral blood mononuclear cells using a RT-PCR method. Reduction of NER gene expression was found in only one of 10 patients with low risk MDS, but in four of 11 patients with high risk MDS. Our data suggest that chromosomal instability and DNA repair defects may be involved in the pathophysiology of disease progression of MDS.

Adult↗

PubMedDate not supplied

Telomerase protects cancer-prone human cells from chromosomal instability and spontaneous immortalization.

Studies were conducted to directly test whether the introduction of telomerase protects cancer-prone human mammary epithelial cells from chromosomal instability and spontaneous immortalization. Using a model for Li Fraumeni Syndrome (LFS), infection of human telomerase resulted in maintenance of telomere lengths, extension of in vitro lifespan, and prevention of spontaneous immortalization. In stark contrast to the spontaneously immortalized LFS cells, cells expressing ectopic telomerase displayed a remarkably stable karyotype and even after >150 population doublings, did not express endogenous telomerase. Since the hTERT-infected and spontaneously immortal LFS cells, like the parental cells, exhibit loss of p53 function, our data suggests that telomere shortening is the primary driving force for the genomic instability characteristic of LFS cells, while p53 inactivation is necessary for triggering the spontaneous immortalization event. Collectively, our data indicate that exogenous telomerase prevents chromosomal instability and spontaneous immortalization of LFS cells, suggesting a unique protective role for telomerase in the progression to immortalization.

Adult↗

PubMed1996

Chromosome instability in untreated adult celiac disease patients.

Spontaneous chromosome aberrations (CAs) and induced fragile sites (FSs) were analysed in 12 untreated adult coeliac disease (CD) patients and 8 healthy controls. Blood lymphocytes from each individual were cultured for 72 h at 37 degrees C in F-10 medium with 5% fetal calf serum and 0.1 ml phytohemagglutinine. FSs were induced by FudR (10 micrograms/ml, 24 h before harvesting) and caffeine (2.2 mM. 6 h before harvest). Spontaneous CAs and FSs were analysed on 30-50 Giemsa-stained and G-banded metaphases. The mean frequencies of spontaneous CAs (abnormal cells, gaps/cell and breaks/cell) of CD patients (0.24 +/- 0.02, 0.21 +/- 0.02 and 0.13 +/- 0.02, respectively) were significantly higher than those of controls (0.04 +/- 0.01, 0.02 +/- 0.01 and 0.02 +/- 0.01, respectively) (p < 0.001). Fourteen spontaneous CAs and 5 FSs specific for CD patients presented a strong coincidence (70%) with bands involved in T- and B-cell malignant lymphoma rearrangements. These findings suggest that CD has chromosome instability affecting specific points that could be related to the high prevalence of malignancies in this disorder.

Adolescent↗

PubMed2005

Chromosomal instability in mouse metastatic pancreatic cancer--it's Kras and Tp53 after all.

A human pancreatic cancer progression model from intraepithelial neoplasia to ductal adenocarcinoma has been proposed. This process has been modeled in the mouse by activation of mutant Kras in pancreatic progenitor cells. In this issue of Cancer Cell, present a modification of their initial model by introducing a mutant Tp53. This combination of genetic alterations leads to rapid and increased frequency of neoplasia progression resulting in pancreatic cancers that manifest chromosomal instability in the presence of apparent intact telomeres. These findings introduce Tp53-mediated chromosomal instability as key event for carcinoma development in this mouse model.

Animals↗

PubMed2002

[Chromosome instability syndromes].

We refer 55 cases of the chromosomal instability syndromes (SCI), diagnosed in patients of our genetical clinics. Problems of early diagnosis can be documented by a discrepancy between the expected number of patients and their relative advanced age at the time when SCI was ascertained. We have also shown that NBS patients can be diagnosed earlier and the disease sufficiently confirmed on the basis of congenital microcephaly and on the direct detection of 657de15 mutation in NBS1 gene. Genealogical analysis of families with SCI revealed a low risk of prenatal selection of affected homozygotes and high cancer prevalence in relative (in NBS families recognized heterozygotes) at young adult age. Due to severe DNA repair disorder and hyperradiosensitivity of affected homozygotes as well as unaffected heterozygotes, conventional diagnostics and treatment protocols of lymphoreticular malignancies in affected homozygotes are prohibited. The use of Nijmegen treatment protocol improved in our patients dramatically their clinical prognosis, which is documented by 6 NBS patients surviving one or two malignancies. Early diagnose of SCI and information for families and their doctors about consequences of DNA repair disorder and about their hyperradiosensitivity is essential for improving the clinical prognosis of SCI patients.

Abnormalities, Multiple↗

PubMed2004

Acquisition of high-level chromosomal instability is associated with integration of human papillomavirus type 16 in cervical keratinocytes.

Whereas two key steps in cervical carcinogenesis are integration of high-risk human papillomavirus (HR-HPV) and acquisition of an unstable host genome, the temporal association between these events is poorly understood. Chromosomal instability is induced when HR-HPV E7 oncoprotein is overexpressed from heterologous promoters in vitro. However, it is not known whether such events occur at the "physiologically" elevated levels of E7 produced by deregulation of the homologous HR-HPV promoter after integration. Indeed, an alternative possibility is that integration in vivo is favored in an already unstable host genome. We have addressed these issues using the unique human papillomavirus (HPV) 16-containing cervical keratinocyte cell line W12, which was derived from a low-grade squamous intraepithelial lesion and thus acquired HPV16 by "natural" infection. Whereas W12 at low passage contains HPV16 episomes only, long-term culture results in the emergence of cells containing integrated HPV16 only. We show that integration of HPV16 in W12 is associated with 3' deletion of the E2 transcriptional repressor, resulting in deregulation of the homologous promoter of the integrant and an increase in E7 protein levels. We further demonstrate that high-level chromosomal instability develops in W12 only after integration and that the forms of instability observed correlate with the physical state of HPV16 DNA and the level of E7 protein. Whereas intermediate E7 levels are associated with numerical chromosomal abnormalities, maximal levels are associated with both numerical and structural aberrations. HR-HPV integration is likely to be a critical event in cervical carcinogenesis, preceding the development of chromosomal abnormalities that drive malignant progression.

Cells, Cultured↗

PubMed2000

p53 abnormality and chromosomal instability in the same breast tumor cells.

To clarify the important role of the tumor-suppressor gene p53 in maintaining genetic integrity, we estimated chromosome instability and staining of overexpressed p53 protein in the same cells of five primary breast carcinomas. The method included both fluorescence immunohistochemistry and fluorescence in situ hybridization (FISH) on sections from formalin-fixed, paraffin-embedded breast cancer tissue. By using a centromeric FISH probe for chromosome 17 on interphase cells in these sections, we showed that cells with abnormal p53 protein expression had a statistically significant higher number of chromosome 17 than did cells with no p53 protein staining in the same samples as well as cells in four other tumor samples with no p53 protein staining. The samples identified positive for p53 abnormality by immunostaining were shown to have p53 mutation by constant denaturing gel electrophoresis analysis and DNA sequencing. These mutated samples were characterized by high DNA index, high S-phase, abnormal karyotype, and aneuploidy. The results strongly implicate p53 mutation as a cause for chromosomal instability and a crucial step in mammary carcinogenesis.

Breast Neoplasms↗

PubMed2005

[Chromosome instability in patients with different forms of cardiomyopathy and their relatives].

Comparative studies on spontaneous and induced by two agents (mytomycin C and Nickel chloride) chromosome instability have been conducted in cultured lymphocytes derived from patients with hypertrophic and dilated forms of cardiomyopathy (HCMP and DCMP) and their relatives compiling a high-risk group to develop mentioned pathologies. In patients with HCMP and DCMP, as well as in their relatives higher levels of spontaneous chromosome instability were found in comparison with the control group (comprising healthy individuals without cardiomyopathic anamnesis). Almost all the affected patients and their relatives revealed tendency to increased aneuploidy and significant elevation of polyploidy when compared with control values. It was demonstrated that nickel chloride-induced chromosome disorders registered more frequently in lymphocytes of the patients and their relatives than in cells of control subjects, but mytomycin C did not have such an affect. We assume to explain the similarity of studied parameters in patients with cardiomyopathy and their relatives as a consequence of identical rearrangements in genome functioning. The revealed analogy should be interpreted as a pre-illness condition for the individuals included in the risk-group.

Aneuploidy↗

PubMed1993

Wiskott-Aldrich syndrome: no evidence of chromosome instability.

Patients with the immune deficiency disorder Wiskott-Aldrich syndrome (WAS) have an increased risk of malignancy, most notably non-Hodgkins lymphoma. To determine whether this susceptibility is due to chromosome instability, cytogenetic analysis was performed on phytohemagglutinin-stimulated lymphocytes from five patients with this disorder. Compared to matched controls, no excess of chromosome aberrations or structural rearrangements was identified. This study does not, therefore, support the view that WAS is a chromosome instability syndrome.

Adolescent↗

PubMed2001

In vivo chromosomal instability and transmissible aberrations in the progeny of haemopoietic stem cells induced by high- and low-LET radiations.

PURPOSE: To study stable and unstable chromosomal aberrations in the haemopoietic cells of CBA/H mice after exposure to both high- and low-LET radiations. MATERIALS AND METHODS: Chromosomal aberrations were scored in the clonal progeny of X-, alpha- or non-irradiated short-term repopulating stem cells using the spleen colony-forming unit (CFU-S) assay, 12 days post-transplantation and in the bone marrow reconstituted by X-, neutron- or non-irradiated exogenous (transplanted) or endogenous (X- or neutron whole-body-irradiated) long-term repopulating stem cells for up to 24 months. RESULTS: Chromosomal instability was demonstrated in 3-6% of cells in all cases. After transplantation of X- or neutron-irradiated bone marrow approximately 8% of cells with stable aberrations were recorded at all times. After 3Gy X- or 0.5 Gy neutron- whole-body irradiation stable aberrations were detected in approximately 17 and 5% of cells respectively. CONCLUSIONS: Chromosomal instability induced in vitro can be transmitted in vivo by transplantation of haemopoietic stem cells exposed to high- or low-LET radiations. Comparable instability can be induced and shown to persist for the remaining lifetime after whole-body irradiation. There was no direct relationship between the expression of stable and unstable aberrations and significant interanimal variation in the expression of both stable and unstable aberrations.

Animals↗

PubMed2004

Chromosome instability in T-cells cultured in the presence of pancuronium or fentanyl.

BACKGROUND: Genomic instability is recognized as a cause of cellular apoptosis and certain drugs that exhibit a proapoptotic effect are also able to induce chromosome damage. Since we found in recent experiments that drugs such as pancuronium and fentanyl exerted an apoptogenic effect on T cells, we studied the capacity of those agents to promote chromosome instability, i.e. chromosome aberrations (CA) and telomeric associations (tas) in peripheral blood lymphocytes. METHODS: Lymphocytes from healthy donors were cultured with pancuronium or fentanyl, using two different concentrations for each drug: 20 and 200 ng/ml for pancuronium and 10 and 30 ng/ml for fentanyl, respectively. Cells were exposed to each concentration of these drugs either for 24 or 48 h. The higher concentration chosen was the same at which we detected the proapoptotic effect in our previous works. Cytogenetic analysis was performed by means of a standard technique and chromosome aberrations or telomeric associations were blindly evaluated by two independent observers. RESULTS: The chromosome aberrations we observed in treated cells were not significantly different from control lymphocytes. However, an unusual rate of telomeric associations (P < 0.001) was detected in cells exposed to both pancuronium and fentanyl, at each concentration tested and at each exposure time of the study. CONCLUSIONS: Fentanyl and pancuronium do not have a direct clastogenic effect on T cultures, but at the same concentrations at which we demonstrated their apoptogenic power, these drugs are able to increase genomic instability through inducing an elevated rate of telomeric associations. Such a capacity could exploit in peripheral T cells the same mitochondrion-mediated signal pathway of apoptosis death.

Adult↗

PubMed1996

No association between p53 status and alpha-particle-induced chromosomal instability in human lymphoblastoid cells.

Previous work has demonstrated that alpha-particle irradiation of primary human bone marrow cells leads to the transmission of chromosomal instability in the descendants of the irradiated cell, although there is some interindividual variation. We have extended these studies to human EBV-transformed lymphoblastoid cell lines in order to establish an in vitro model system. The five cell lines analyzed, including one from a Fanconi anaemia patient, exhibited high levels of persistent chromatid aberrations up to approximately 40 cell generations after alpha-irradiation. The p53 status of the cell lines was defined according to whether cellular p53 levels were induced by irradiation, translocated to the nucleus and were able to bind a p53 DNA consensus recognition sequence in vitro. Together with the primary bone marrow cell studies, we conclude that alpha-particle induced chromosomal instability is independent of the p53 status of the cell as defined in these studies.

Alpha Particles↗

PubMed2005

The association of DNA-dependent protein kinase activity with chromosomal instability and risk of cancer.

The DNA double-strand breaks (DSBs) repair pathway has been implicated in maintaining genomic integrity via suppression of chromosomal rearrangements. DNA-dependent protein kinase (DNA-PK) has an important role with DNA DSBs repair. In this study, 93 of untreated cancer patients and 41 of cancer-free healthy volunteers were enrolled. Peripheral blood was collected, separated and centrifuged; DNA-PK activity was measured by DNA-pull-down assay. The expressions of DNA-PKcs, Ku70 and Ku86 were examined by RT-PCR assay and western blotting. Chromosomal aberrations were examined by cytogenetic methods. DNA-PK activities of peripheral blood lymphocytes (PBL) in patients with uterine cervix or breast cancer were significantly lower than those in normal volunteers. Age and smoking had no association with DNA-PK activity, whereas DNA-PK activity and the expression of Ku70, Ku86 and DNA-PKcs in RT-PCR were interrelated. A similar tendency was seen in western blot assay but less clear than in RT-PCR. Therefore, the association between DNA-PK activity and expression of DNA-PK in protein level could not be concluded. The frequency of chromosome aberration, such as dicentric chromosomes and excess fragment increased as the DNA-PK activity decreased. In conclusion, DNA-PK activity is associated with chromosomal instability. DNA-PK activity in PBL is associated with risk of breast and uterine cervix cancer. DNA-PK activity in PBL can be used to select individuals for whom an examination should be performed because of their increased susceptibility to breast and uterine cervix cancer.

Adult↗

PubMed1988

Patients with an inherited syndrome characterized by immunodeficiency, microcephaly, and chromosomal instability: genetic relationship to ataxia telangiectasia.

Fibroblast cultures from six unrelated patients having a familial type of immunodeficiency combined with microcephaly, developmental delay, and chromosomal instability were studied with respect to their response to ionizing radiation. The cells from five of them resembled those from individuals with ataxia telangiectasia (AT) in that they were two to three times more radiosensitive on the basis of clonogenic cell survival. In addition, after exposure to either X-rays or bleomycin, they showed an inhibition of DNA replication that was less pronounced than that in normal cells and characteristic of AT fibroblasts. However, the patients are clinically very different from AT patients, not showing any signs of neurocutaneous symptoms. Genetic complementation studies in fused cells, with the radioresistant DNA synthesis used as a marker, showed that the patients' cells could complement representatives of all presently known AT complementation groups. Furthermore, they were shown to constitute a genetically heterogeneous group as well. It is concluded that these patients are similar to AT patients with respect to cytological parameters. The clinical differences between these patients and AT patients are a reflection of genetic heterogeneity. The data indicate that the patients suffer from a chromosome-instability syndrome that is distinct from AT.

Ataxia Telangiectasia↗

PubMed2003

Chromosome instability and progression in urothelial cell carcinoma of the bladder.

Superficial urothelial cell carcinoma (UCC) is a heterogeneous group of neoplasia with an unpredictable clinical course. Numerical alterations of chromosomes 7, 9 and 17 in superficial and invasive UCCs were analysed to evaluate the importance of chromosome instability in the progression of these tumours. Our sample consisted of 75 patients (47 with superficial and 28 with invasive bladder tumours). In situ hybridization using centromeric probes for chromosomes 7, 9 and 17 was done for the chromosome analysis in paraffin-embedded tissues. From the results obtained it can be concluded that losses of genetic material seem to be important early events in the carcinogenesis of the urothelium, but during progression of UCCs there seems to be a selection of those cells with gains of genetic material. This chromosome instability may be due to the acquisition of mechanisms involved in aneuploidization, namely p53 function disorders.

Adult↗