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Results for “Genomic instability”

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At least 487 records · Page 27Linked to original sources
PubMed2004

Dynamics of telomere erosion and its association with genome instability in myelodysplastic syndromes (MDS) and acute myelogenous leukemia arising from MDS: a marker of disease prognosis?

Telomere length was evaluated by terminal repeat fragment method (TRF) in 50 patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) arising from MDS and in 21 patients with untreated primary AML to ascertain, whether telomere erosion was associated with progression of MDS towards overt leukemia. Heterogeneity of TRF among MDS FAB subgroups (P=0.004) originated from its shortening in increased number of patients during progression of the disease. Chromosomal aberrations were present in 32% MDS patients with more eroded telomeres (P=0.022), nevertheless a difference between mean TRF in the subgroups with normal and abnormal karyotype diminished during progression of MDS. A negative correlation between individual TRF and IPSS value (P=0.039) showed that telomere dynamics might serve as a useful prognostic factor for assessment of an individual MDS patient's risk and for decision of an optimal treatment strategy.

Adolescent↗
PubMed2004

Genome instability in ataxia telangiectasia (A-T) families: camptothecin-induced damage to replicating DNA discriminates between obligate A-T heterozygotes, A-T homozygotes and controls.

Previously we used the topoisomerase I inhibitor camptothecin (CPT), which kills mainly S-phase cells primarily by inducing double strand breaks (DSBs) in replication forks, to show that ataxia telangiectasia (A-T) fibroblasts are defective in the repair of this particular subclass of DSBs. CPT treated A-T cells reaching G2 have abnormally high levels of chromatid exchanges, viewed as prematurely condensed G2 chromosomes (G2 PCC), compared with normal cells where aberrations are mostly chromatid breaks. Here we show that A-T lymphoblastoid cells established from individuals with different mutations in the ATM gene also exhibit increased levels of chromosomal exchanges in response to CPT, indicating that the replication-associated DSBs are misrepaired in all these cells. From family studies we show that the presence of a single mutated allele in obligate A-T heterozygotes leads to intermediate levels of chromosomal exchanges in CPT-treated lymphoblastoid cells, thus providing a functional and sensitive assay to identify these individuals.

Ataxia Telangiectasia↗
PubMed2005

Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1.

Mre11, Rad50, and Nbs1 form an evolutionarily conserved protein complex (Mre11-Rad50-Nbs1, MRN) that has been proposed to function as a DNA damage sensor. Hypomorphic mutations in Mre11 and Nbs1 result in the human ataxia-telangiectasia-like disorder and Nijmegen breakage syndrome (NBS), respectively. In contrast, complete inactivation of Mre11, Rad50, or Nbs1 leads to early embryonic lethality, suggesting that the hypomorphic mutations may fail to reveal some of the essential functions of MRN. Here, we use Cre-loxP-mediated recombination to restrict Nbs1 deletion to B lymphocytes. We find that disruption of Nbs1 results in the accumulation of high levels of spontaneous DNA damage, impaired proliferation, and chromosomal endoreduplication. Moreover, we show that Ig class-switch recombination (CSR) is diminished in Nbs1-deficient B cells. The CSR defect is B cell-intrinsic, independent of switch-region transcription, and a consequence of inefficient recombination at the DNA level. Our findings reveal that Nbs1 is critical for efficient Ig CSR and maintenance of the integrity of chromosomal structure and number.

Animals↗
PubMed2004

Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27, and antiestrogens in breast cancer.

The deregulated expression of cyclin E as measured by the overexpression of its low molecular weight (LMW) isoforms is a powerful predictor of poor outcome in patients with breast cancer. The mechanism by which these LMW forms give tumor cells a growth advantage is not known and is the subject of this article. In this article, we provide the pathobiological mechanisms of how these LMW forms are involved in disease progression. Specifically, we show that overexpression of the LMW forms of cyclin E but not the full-length form in MCF-7 results in (a) their hyperactivity because of increased affinity for cdk2 and resistance to inhibition by the cyclin-dependent kinase inhibitors p21 and p27, (b) resistance to the growth inhibiting effects of antiestrogens, and (c) chromosomal instability. Lastly, tumors from breast cancer patients overexpressing the LMW forms of cyclin E are polyploid in nature and are resistant to endocrine therapy. Collectively, the biochemical and functional differences between the full-length and the LMW isoforms of cyclin E provide a molecular mechanism for the poor clinical outcome observed in breast cancer patients harboring tumors expressing high levels of the LMW forms of cyclin E. These properties of the LMW forms cyclin E suggest that they are not just surrogate markers of poor outcome but bona fide mediators of aggressive disease and potential therapeutic targets for patients whose tumors overexpress these forms.

Adult↗
PubMed2006

Genomic instability analysis of urine sediment versus tumor tissue in transitional cell carcinoma of the urinary bladder.

Microsatellite alterations are a common feature of neoplastic cells. Our study aimed to compare the profile of microsatellite DNA alterations in tumor tissue and urine sediment at 12 selected microsatellite loci in transitional cell carcinoma of the bladder, and to determine which of the 12 markers or combination of markers has potential for the non-invasive diagnosis of bladder cancer. DNA alterations were examined using microsatellite markers on chromosomes 2p, 3p, 8p, 9p, 9q, 12q, 13q, 17p and 18q in 38 patients, including 12 with superficial Ta/T1 and 26 with muscle invasive T2-T4 bladder tumors. Microsatellite instability was a rare event in comparison with loss of heterozygosity and was related to a low rate of defects in mismatch repair genes. The sensitivity of microsatellite analysis was 75% (9/12) for Ta/T1 tumors and 69% (18/26) for T2-T4 tumors. Two tetranucleotide markers, D9S242 and D9S252, when combined, displayed microsatellite alterations in 59% (16/27) of microsatellite analysis-positive patients. DNA alterations were not detected in 21 non-tumor specimens. Twenty of 51 (39%) tumor DNA alterations were re-detected in urine sediments, and 7 alterations found in urine sediments were not found in the corresponding tumor specimens. No association was found between the DNA alterations and any of the prognostic parameters. However, the overall survival correlated with microsatellite alterations (P=0.04, log-rank test). These data suggest that markers at tetranucleotide repeats on chromosome 9q have particular diagnostic potential in bladder cancer. Moreover, microsatellite analysis is suitable for the selection of patients with a less favorable outcome.

Aged↗
PubMed2006

Werner syndrome: molecular insights into the relationships between defective DNA metabolism, genomic instability, cancer and aging.

Werner syndrome is a segmental progeroid disease characterized by increased cancer and acceleration of specific age-related phenotypes, due to loss of a protein known as WRN. Extensive research over the last decade has revealed much about WRN biochemistry and the etiology of Werner syndrome. WRN possesses multiple DNA-dependent enzymatic activities (ATPase, helicase, exonuclease, and strand annealing) and interacts with factors having established roles in DNA metabolic pathways. Although the exact functions of WRN remain unclear, accumulating evidence points to roles in proper resolution of replication blockage and in telomere maintenance. If WRN function is lost (as exemplified in cells from Werner patients), problems with replication and DNA damage processing arise, probably resulting in an increased number or persistence of strand breaks. In turn, these events lead to chromosomal and telomeric abnormalities or activate checkpoints that bring about early senescence or increased apoptosis. Thus, elevated cancer incidence associated with Werner syndrome is due to increased chromosomal changes, while the accelerated aging characteristics probably stem from telomere dysfunction leading to accumulation of non-functional senescent cells or excessive apoptotic cell death over time. More research is needed to determine whether these specific DNA-dependent mechanisms contribute to development of aging characteristics in normal individuals.

Adenosine Triphosphatases↗
PubMed2005

Genomic instability of human mammary epithelial cells overexpressing a truncated form of EMSY.

The EMSY gene encodes a protein that interacts with Brca2 and is amplified in some sporadic cases of human breast cancer. To examine whether overexpression of EMSY would mimic the chromosome instability phenotype that is associated with the loss of Brca2 function, we constructed a lentiviral vector (Lenti-EMSY/GFP) that encodes a truncated form of the Emsy protein, including its Brca2-interacting domain, and green fluorescent protein (GFP) and used it to transduce human telomerase-immortalized human breast epithelial (184-hTert) cells, which have a nearly normal karyotype. At passage 5 after transduction, 39 (26%) of 150 EMSY/GFP-transduced metaphase cells contained at least one structural chromosomal abnormality compared with 19 (13%) of 150 GFP-transduced metaphase cells (P = .003, chi-square test); at passage 10, the corresponding frequencies were 42% and 15%, respectively (P < .001). Mitomycin C also produced a severalfold higher frequency of chromosome breaks in the EMSY/GFP-transduced cells than in the control cells. These results support the hypothesis that EMSY overexpression can play a role in the genesis of human breast cancer.

Aneuploidy↗
PubMed2005

Disruption of murine Mus81 increases genomic instability and DNA damage sensitivity but does not promote tumorigenesis.

The Mus81-Eme1 endonuclease is implicated in the efficient rescue of broken replication forks in Saccharomyces cerevisiae and Schizosaccharomyces pombe. We have used gene targeting to study the function of the Mus81-Eme1 endonuclease in mammalian cells. Mus81-deficient mice develop normally and are fertile. Surprisingly, embryonic fibroblasts from Mus81(-/-) animals fail to proliferate in vitro. This proliferation defect can be rescued by expression of the papillomavirus E6 protein that promotes degradation of p53. When grown in culture, Mus81(-/-) cells have elevated levels of DNA damage, acquire chromosomal aberrations, and are hypersensitive to agents that generate DNA cross-links. In contrast to the situation in yeast, murine Mus81 is not required for replication restart following camptothecin treatment. Mus81(-/-) mice and cells are hypersensitive to DNA cross-linking agents. Cross-link-induced double-strand break formation is normal in Mus81(-/-) cells, but the resolution of repair intermediates is not. The persistence of Rad51 foci in Mus81(-/-) cells suggests that Mus81 acts at a late step in the repair of cross-link-induced lesions. Despite these defects, Mus81(-/-) mice do not show increased predisposition to lymphoma or any other malignancy in the first year of life.

Animals↗
PubMed2004

Large-scale mitochondrial DNA deletion mutations and nuclear genome instability in human breast cancer.

Deletion mutations in mitochondrial (mt) DNA (mtDNA) as well as microsatellite instability (MSI) and loss of heterozygosity (LOH) in nuclear DNA (nDNA) exist in human cancer. We determined if: (1) large-scale mtDNA deletion mutations were present in cancerous and not in normal breast tissue, and (2) combining mt- and nDNA findings would provide complementary information to identify breast cancer. Thirty-nine matched breast cancer/histologically normal and 23 "true" normal tissue samples from women without breast cancer were microdissected and DNA extracted. 4977, approximately 3938, approximately 4388 and approximately 4576bp deletions were observed, with the 4576bp deletion being present in 0% of true normal, 13% of histologically normal specimens from a cancerous breast and 77% of breast cancers. The other three deletions were not specific to a breast containing cancer. LOH was found in 66.7% and MSI in 38.5% of samples. 38/39 (97.4%) tumors had at least one nDNA or 4576bp mtDNA alteration, suggesting that mt- and nDNA analysis provides complementary information in breast cancer detection. The 4576bp deletion appears to indicate cancer in the breast. The higher mtDNA copy number in cancer coupled with a mtDNA deletion mutation which appears specific for breasts which contain cancer may prove to be a good target to screen for cancer in the breast, including specimens of low and/or mixed cellularity.

Alleles↗
PubMed2006

Role of genomic instability and p53 in AID-induced c-myc-Igh translocations.

Chromosomal translocations involving the immunoglobulin switch region are a hallmark feature of B-cell malignancies. However, little is known about the molecular mechanism by which primary B cells acquire or guard against these lesions. Here we find that translocations between c-myc and the IgH locus (Igh) are induced in primary B cells within hours of expression of the catalytically active form of activation-induced cytidine deaminase (AID), an enzyme that deaminates cytosine to produce uracil in DNA. Translocation also requires uracil DNA glycosylase (UNG), which removes uracil from DNA to create abasic sites that are then processed to double-strand breaks. The pathway that mediates aberrant joining of c-myc and Igh differs from intrachromosomal repair during immunoglobulin class switch recombination in that it does not require histone H2AX, p53 binding protein 1 (53BP1) or the non-homologous end-joining protein Ku80. In addition, translocations are inhibited by the tumour suppressors ATM, Nbs1, p19 (Arf) and p53, which is consistent with activation of DNA damage- and oncogenic stress-induced checkpoints during physiological class switching. Finally, we demonstrate that accumulation of AID-dependent, IgH-associated chromosomal lesions is not sufficient to enhance c-myc-Igh translocations. Our findings reveal a pathway for surveillance and protection against AID-dependent DNA damage, leading to chromosomal translocations.

Animals↗
PubMed2003

Large-scale genomic instability predicts long-term outcome for women with invasive stage I ovarian cancer.

BACKGROUND: The objective was to evaluate the value of DNA ploidy using high-resolution image cytometry in predicting long-term survival of patients with early ovarian cancer. PATIENTS AND METHODS: A retrospective analysis of 284 cases with FIGO stage I ovarian carcinoma treated during the period 1982-1989 was performed. Clinical follow-up information was available for all patients. RESULTS: Patients with diploid and tetraploid tumors had a 10-year relapse-free survival of 95% and 89%, respectively, compared with 70% and 29% for polyploid and aneuploid tumors, respectively. DNA ploidy analysis was the strongest predictor of survival in multivariate analysis (diploid/tetraploid versus polyploid/aneuploid; relative hazard 9.0) followed by histological grade, including clear cell tumors in the group of poorly differentiated tumors (grade 1-2 versus grade 3 or clear cell; relative hazard 2.7), and FIGO stage (Ib/Ic versus Ia; relative hazard 2.0). In a stratified Kaplan-Meier analysis, patients with grade 1-2, diploid or tetraploid tumors had a 10-year relapse-free survival of 95%, forming a low-risk group. Patients with grade 3 or clear cell, diploid or tetraploid tumors had 10-year relapse-free survival of 86%, forming an intermediate-risk group, while all patients with aneuploid/polyploid tumors formed a high-risk group, with 10-year relapse-free survival of 34%. CONCLUSIONS: This study points to the importance of including DNA ploidy analysis by image cytometry when selecting patients with early ovarian cancer for adjuvant treatment after surgery.

Adult↗
PubMed2004

DNA breaks promote genomic instability by impeding proper chromosome segregation.

BACKGROUND: Unrepaired DNA double-stranded breaks (DSBs) can result in the whole or partial loss of chromosomes. Previously, we showed that the ends of broken chromosomes remain associated. Here, we have examined the machinery that holds broken chromosome ends together, and we have explored the behavior of broken chromosomes as they pass through mitosis. RESULTS: Using GFP-localized arrays flanking an HO endonuclease site, we examined the association of broken chromosome ends in yeast cells that are checkpoint-arrested in metaphase. This association is partially dependent upon Rad50 and Rad52. After 6-8 hr, cells adapted to the checkpoint and resumed mitosis, segregating the broken chromosome. When this occurred, we found that the acentric fragments cosegregated into either the mother or daughter cell 95% of the time. Similarly, pedigree analysis showed that postmitotic repair of a broken chromosome (rejoining the centric and acentric fragments) occurred in either the mother or daughter cell, but rarely both, consistent with a model in which both acentric sister chromatid fragments are passaged into the same nucleus. CONCLUSIONS: These data suggest two related phenomena: an intrachromosomal association that holds the halves of a single broken sister chromatid together in metaphase and an interchromosomal force that tethers broken sister chromatids to each other and promotes their missegregation. Strikingly, the interchromosomal association of DNA breaks also promotes the missegregation of centromeric chromosomal fragments, albeit to a lesser extent than acentric fragments. The DNA break-induced missegregation of acentric and centric chromosome fragments provides a novel mechanism for the loss of heterozygosity that precedes tumorigenesis in mammalian cells.

Chromosome Breakage↗
PubMedDate not supplied

Genomic instability in scleroderma.

Scleroderma is an enigmatic rheumatic disorder of uncertain etio-pathogenesis. Cancer has an approximately two-fold higher incidence in scleroderma patients than in the general population. There are preliminary data of acquired genetic damage in scleroderma but the significance of these observations are uncertain. To determine somatic mutation frequency at the glycophorin-A (GPA) locus in patients with limited and diffuse cutaneous scleroderma. The GPA assay measures the total somatic mutation frequency (Vf), composed of gene inactivating mutations (NO) and mutations arising from mitotic recombination (NN) in individuals heterozygous for the GPA MN blood group. Mutation frequency was determined using a validated GPA flow cytometric assay using fluorescent labeled monoclonal antibodies specific for the GPA blood groups M and N. This assay detects and enumerates progeny of red blood cell (rbc) precursor cells which have acquired genetic damage resulting in a loss of expression of one of the GPA alleles. It was found that patients with scleroderma (n = 23) had significantly elevated Vf as compared with young healthy controls (p < 0.001) and elderly controls (p = 0.03). Patients with diffuse scleroderma had higher mean Vf as compared with limited scleroderma (p = 0.055). In comparison with controls, patients with scleroderma exhibit a higher proportion of mitotic recombinant mutations than inactivating mutations (p < 0.002). There was no correlation between Vf and disease duration, age at onset or autoantibody status. We have documented evidence of acquired genetic damage at the GPA locus in scleroderma. Evidence of acquired genetic damage in this disorder may be importance in explaining both the etio-pathogenesis of scleroderma and the association of scleroderma with cancer.

Adolescent↗
PubMedDate not supplied

[Genome instability].

The paper deals with the various manifestations and the role of genome changes, mainly in eukaryotes. I. Hereditary changes: 1) multiplication of genes in animals; 2) multiplication of genes in prokaryotes; 3) microsymbionts, mobile elements and supermutability; 4) extrachromosomal element delta in Drosophila; 5) hybrid dysgenesis in Drosophila; 6) mobile and unstable genes in drosophila; 7) controlling elements in planrs. II. Genome changes as a regulatory factor of genetic activity: 1) immunoglobulin genes; 2) mating types in yeast; 3) the inversion mechanism of switching gene activity in prokaryotes; 4) ribosomal and histone genes; 5) changes of DNA fractions in ontogenesis; 6) regulation of genome changes.

Animals↗
PubMed2003

Genomic instability and endoreduplication triggered by RAD17 deletion.

Cell cycle checkpoints are critical for genomic stability. Rad17, a component of the checkpoint clamp loader complex (Rad17/Rfc2-5), is required for the response to DNA damage and replication stress. To explore the role of Rad17 in the maintenance of genomic integrity, we established somatic conditional alleles of RAD17 in human cells. We find that RAD17 is not only important for the Atr-mediated checkpoint but is also essential for cell viability. Cells lacking RAD17 exhibited acute chromosomal aberrations and underwent endoreduplication at a high rate. Therefore, RAD17 links the checkpoint to ploidy control and is essential for the maintenance of chromosomal stability.

Blotting, Southern↗
PubMed2002

LINE drive. retrotransposition and genome instability.

The LINE-1 (L1) retrotransposon, the most important human mobile element, shapes the genome in many ways. Now two groups provide evidence that L1 retrotransposition is associated with large genomic deletions and inversions in transformed cells. If these events occur at a similar frequency in vivo, they have had a substantial effect on human genome evolution.

Animals↗
PubMed1999

Germline mutation and genome instability.

Colorectal tumorigenesis has been associated with the progressive acquisition of a variety of genomic alterations in neoplastic cells. In 5-10% of cases, a strong family history of cancer suggests a major predisposition, either familial adenomatous polyposis (FAP) or HNPCC syndrome. In 1987, the gene responsible for FAP was localized on chromosome 5q. In 1991, the International Collaborative Group on HNPCC set stringent criteria for the diagnosis of HNPCC, to homogenize families that should be entered in large linkage analyses. In the past five years, five MMR genes could be identified as the site of germline mutations associated with a HNPCC syndrome (MSH2, MLH1, PMS1, PMS2, and MSH6). The TGFbeta RII gene has been found mutated at the germline level in a small number of HNPCC patients. The DNA mismatch repair pathway is essential for the correct maintenance of genetic information. The slippage occurs usually at microsatellite loci and the defect of one MMR gene leads to the accumulation of replication errors in such deficient cells. The tumours that exhibit the highest frequency of RER at microsatellite loci, thus termed RER+, account for 10-15% of all colorectal cancers, and for 92% of those developed in a context of a HNPCC syndrome.

Animals↗
PubMed2003

The role of DNA breaks in genomic instability and tumorigenesis.

DNA double-strand breaks (DSBs) represent dangerous chromosomal lesions that can lead to mutation, neoplastic transformation, or cell death. DSBs can occur by extrinsic insult from environmental sources or may occur intrinsically as a result of cellular metabolism or a genetic program. Mammalian cells possess potent and efficient mechanisms to repair DSBs, and thus complete normal development as well as mitigate oncogenic potential and prevent cell death. When DSB repair (DSBR) fails, chromosomal instability results and can be associated with tumor formation or progression. Studies of mice deficient in various components of the non-homologous end joining pathway of DSBR have revealed key roles in both the developmental program of B and T lymphocytes as well as in the maintenance of general genome stability. Here, we review the current thinking about DSBs and DSBR in chromosomal instability and tumorigenesis, and we highlight the implications for understanding the karyotypic features associated with human tumors.

Animals↗