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Results for “Genomic instability”

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At least 91 records · Page 5Linked to original sources
PubMed2005

Characterization of genomic instability in ulcerative colitis neoplasia leads to discovery of putative tumor suppressor regions.

Ulcerative colitis (UC) is an inflammatory disease of the colon that is associated with increased risk of colorectal cancer associated with genomic instability. We have previously demonstrated that genomic instability is present in UC patients with colonic neoplasia, and hypothesized that the chromosomal alterations may be taking place in regions that are susceptible to mutation or that provide a growth advantage to a cell undergoing neoplastic transformation. In this study, we used two polymerase chain reaction (PCR)-based DNA fingerprinting techniques (arbitrarily primed PCR and inter-simple-sequence-repeat PCR) to study the process of genomic instability. The two techniques of DNA fingerprinting cross-validate the instability observed in these studies. We analyzed the molecular basis of 10 commonly altered DNA bands obtained from DNA fingerprints of biopsies from various histologic grades of UC patients with dysplasia or cancer (UC Progressors). We determined that the band changes in the fingerprint truly represent changes in DNA sequence, and that the fingerprinting provides highly reproducible results. Furthermore, our investigation revealed that 40% of alterations involve repetitive sequences. Two frequently deleted sequences in 6q27 and 2q14 were studied further because they were frequently abnormal in the dysplastic and nondysplastic tissue of UC Progressors. The losses from 6q27 and 2q14 were confirmed by loss of heterozygosity and real-time PCR analysis. Both of these regions in chromosomes 6 and 2 are surrounded by highly repetitive and mobile LINE-1 elements, possibly making the region susceptible to mutational change. These regions were affected (lost) in UC Progressors but not in UC patients who were neoplasia free. Loss of heterozygosity at 6q27 has been described in ovarian and other cancers, while the 2q14 region has been implicated in prostate and sporadic colon cancers. Both regions are likely to contain tumor-suppressor genes. In conclusion, the genomic instability in UC Progressors can occur in regions that are susceptible to change and are locations of putative tumor-suppressor genes.

Colitis, Ulcerative↗
PubMed2004

Destructive cycles: the role of genomic instability and adaptation in carcinogenesis.

Classical theories of carcinogenesis postulate that the accumulation of several somatic mutations is responsible for oncogenesis. However, these models do not explain how non-mutagenic carcinogens cause cancer. In addition, known mutation rates appear to be insufficient to account for observed cancer rates. Moreover, the current theory doesn't easily account for the long latencies observed in human cancers. Proponents of an aneuploidy-driven theory of carcinogenesis suggest that genomic instability has a causative role in carcinogenesis. In support of this theory, pre-neoplastic cells frequently display genomic instability while normal cells do not. Data obtained from a variety of model organisms have revealed that disruption of the cell cycle controls required for homeostasis results in the acquisition of genomic instability. Subsequently, this genomic instability becomes self-propagating via 'destructive cycles' and provides a medium for cellular selection and adaptation. Genomic instability allows numerous genetic and epigenetic alterations to accumulate during carcinogenesis without markedly changing phenotype until they are qualitatively or quantitatively sufficient to be selectively advantageous in the tumor microenvironment. Observations of adaptation in tumor cell populations and application of chaos theory may help elucidate the mechanism that drives the enormous genetic heterogeneity observed in tumors and provide insights into the development of new therapeutic cancer interventions and treatments.

Animals↗
PubMed2001

Persistent genomic instability in the yeast Saccharomyces cerevisiae induced by ionizing radiation and DNA-damaging agents.

A "hypermutable" genome is a common characteristic of cancer cells, and it may contribute to the progressive accumulation of mutations required for the development of cancer. It has been reported that mammalian cells surviving exposure to gamma radiation display several highly persistent genomic instability phenotypes which may reflect a hypermutability similar to that seen in cancer. These phenotypes include an increased mutation frequency and a decreased plating efficiency, and they continue to be observed many generations after the radiation exposure. The underlying causes of this genomic instability have not been fully determined. We show here that exposure to gamma radiation and other DNA-damaging treatments induces a similar genomic instability in the yeast Saccharomyces cerevisiae. A dose-dependent increase in intrachromosomal recombination was observed in cultures derived from cells surviving gamma irradiation as many as 50 generations after the exposure. Increased forward mutation frequencies and low colony-forming efficiencies were also observed. Persistently elevated recombination frequencies in haploid cells were dominant after these cells were mated to nonirradiated partners, and the elevated recombination phenotype was also observed after treatment with the DNA-damaging agents ultraviolet light, hydrogen peroxide, and ethyl methanesulfonate. Radiation-induced genomic instability in yeast may represent a convenient model for the hypermutability observed in cancer cells.

DNA Damage↗
PubMed2005

The death-inducing effect and genomic instability.

Exposure to ionizing radiation can induce a heritable change in the unirradiated progeny of irradiated cells. This non-targeted effect of ionizing radiation manifests as genomic instability, and although there is some debate as to the role of genomic instability in the carcinogenic process, it is thought by some to be an early step in radiation carcinogenesis. Although the mechanism of induction of genomic instability is not clearly understood, evidence suggests that secreted factors from irradiated cells may be involved. We have previously identified another non-targeted effect of ionizing radiation, the death-inducing effect. Exposure of unirradiated GM10115 cells to medium from chromosomally unstable clones was generally found to be cytotoxic. However, occasionally cells will survive in medium from unstable clones and can be clonally expanded. The absolute yield of survivors is independent of the initial number of cells plated when cell densities reached 5,000 or more cells/dish. After cytogenetic analysis of the surviving colonies, we found chromosomal instability in three of 40 clones analyzed, while some clones exhibited increased micronucleus frequency and HPRT mutation frequency. These data suggest that our chromosomally unstable GM10115 cells secrete factors that are cytotoxic to the majority of stable, parental cells but are also capable of inducing a heritable change in some of the survivors that can manifest as delayed genomic instability. These results suggest a mechanism whereby instability can be perpetuated through the influences of potentially cytotoxic factors produced by genomically unstable clones.

Animals↗
PubMed2003

End resection initiates genomic instability in the absence of telomerase.

Telomere dysfunction causes genomic instability. However, the mechanism that initiates this instability when telomeres become short is unclear. We measured the mutation rate and loss of heterozygosity along a chromosome arm in diploid yeast that lacked telomerase to distinguish between mechanisms for the initiation of instability. Sequence loss was localized near chromosome ends in the absence of telomerase but not after breakage of a dicentric chromosome. In the absence of telomerase, the increase in mutation rate is dependent on the exonuclease Exo1p. Thus, exonucleolytic end resection, rather than chromosome fusion and breakage, is the primary mechanism that initiates genomic instability when telomeres become short.

Base Sequence↗
PubMed2004

Mosaic eyes, genomic instability mutants, and cancer susceptibility.

We now know that genomic instability contributes to cancer. The zebrafish mosaic eye assay developed by George Streisinger takes advantage of the organism's transparency to provide an excellent assay for detecting somatic mutation. This assay allowed us to identify zebrafish mutants with increased frequencies of somatic mutation and spontaneous cancer. Here, we have described details of mutagenesis, the basis and practical use of the mosaic eye assay, and the histological methods used to study genomic instability mutants and cancer susceptibility. These techniques should prove useful to other zebrafish researchers, as they are broadly applicable to many other biological investigations of embryos, larvae, and adult zebrafish.

Animals↗
PubMed2002

Mitochondrial dysfunction leads to telomere attrition and genomic instability.

Mitochondrial dysfunction and oxidative stress have been implicated in cellular senescence, apoptosis, aging and aging-associated pathologies. Telomere shortening and genomic instability have also been associated with replicative senescence, aging and cancer. Here we show that mitochondrial dysfunction leads to telomere attrition, telomere loss, and chromosome fusion and breakage, accompanied by apoptosis. An antioxidant prevented telomere loss and genomic instability in cells with dysfunctional mitochondria, suggesting that reactive oxygen species are mediators linking mitochondrial dysfunction and genomic instability. Further, nuclear transfer protected genomes from telomere dysfunction and promoted cell survival by reconstitution with functional mitochondria. This work links mitochondrial dysfunction and genomic instability and may provide new therapeutic strategies to combat certain mitochondrial and aging-associated pathologies.

Animals↗
PubMed2002

c-MYC overexpression in Ba/F3 cells simultaneously elicits genomic instability and apoptosis.

Overexpression of c-Myc in tumors is usually associated with cell proliferation and increased susceptibility to apoptosis. Concomitantly, c-Myc contributes to tumorigenesis by its ability to destabilize the cellular genome. Here, we examined whether c-Myc induces genomic instability and apoptosis in c-Myc-activated cells. Wild-type Myc (wt-Myc) and two mutated Myc myc box II proteins (mt-Myc) were overexpressed in IL3-dependent murine Ba/F3 cells. As expected, wt-Myc triggered apoptosis in absence of IL3. Standard karyotyping, spectral karyotyping, and fluorescent in situ hybridization (FISH) were performed before and after c-Myc activation. Structural and numerical genomic instability was detected 48 h after wt-Myc activation and included gene amplification, the formation of extrachromosomal elements (EEs), chromosome breakage, deletions, increased aneuploidy, and polyploidization. Interestingly, some cells simultaneously displayed genomic instability and apoptosis. Both wt- and mt-Myc proteins were equally potent promoters of genomic instability. However, only wt-Myc simultaneously induced genomic instability and apoptosis. Mt-Myc proteins failed to induce apoptosis, thereby generating a strong imbalance towards the survival of genomically unstable cells.

Aneuploidy↗
PubMed1994

In vivo enhancement of genomic instability in minisatellite sequences of mouse C3H/10T1/2 cells transformed in vitro by X-rays.

The level of genomic instability was determined during tumor development in vivo. Genomic rearrangements, a marker of genomic instability, was measured in mouse C3H/10T1/2 cells transformed in vitro by X-rays with a DNA fingerprinting assay. Three transformed clones isolated from type III foci were divided into two groups. Cells from the first group were injected s.c. into syngeneic and nonimmunosuppressed C3H mice. After 3 to 5 months, the tumors were excised, and the neoplastic cells were isolated and subcloned. Cells from the second group were incubated in vitro for 25 passages (about 6 months) to approximate the number of cell divisions occurring in the tumor, and then they were subcloned. DNA was extracted from subclones grown in vitro and in vivo and analyzed with the DNA fingerprinting assay. A high frequency of genomic rearrangements (50-100%) was found in subclones derived from tumors that arose in vivo, whereas the frequency was very low (< 10%) among subclones passaged in vitro, suggesting that genetic instability may be enhanced by factors present in the C3H mouse. In one clone (F-17) genomic instability appeared to be activated and down regulated. The high frequency of instability found in tumor cell subclones did not appear to result from an in vivo selection of a more tumorigenic subpopulation of cells present in the original clone prior to injection in the animal. This enhancement of genomic instability occurring in vivo could be required to complete the process of transformation to tumorigenicity and allow the neoplastic cells to adapt to a new environment.

Animals↗
PubMed2006

Mitochondrial dysfunction, persistently elevated levels of reactive oxygen species and radiation-induced genomic instability: a review.

Radiation-induced genomic instability (RIGI) challenges the long-standing notion that radiation's effects derive solely from nuclear impact. In RIGI it is the unirradiated progeny that can display phenotypic changes at delayed times after irradiation of the parental cell. RIGI might well provide the driving force behind the development of radiation-induced tumorigenesis as most cancer cells even in pre-neoplastic states display multiple genetic alterations. Thus, understanding RIGI may help elucidate the mechanisms underlying radiation-induced carcinogenesis. One characteristic of clones of genetically unstable cells is that many exhibit persistently increased levels of reactive oxygen species (ROS). Furthermore, oxidants enhance and antioxidants diminish radiation-induced instability. However, much about the mechanisms behind the initiation and perpetuation of RIGI remains unknown and we examine the evidence for the hypothesis that oxidative stress and mitochondrial dysfunction may be involved in perpetuating the unstable phenotype in some cell clones surviving ionizing radiation.

Animals↗
PubMed2002

Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a.

Genomic instability has been a recognized feature of many human tumors for decades. Until recently, however, there was little insight into potential mechanisms for this phenomenon. Recent work has shown first, that increased centrosome numbers (also referred to as centrosome amplification) often accompany genomic instability and second, that when centrosome numbers are increased, cells become genetically unstable. Deletion of Gadd45a leads to centrosome amplification and consequent abnormal mitosis and aneuploidy. Gadd45a is known to be involved in a G2 checkpoint and may be involved in the normal progression from G2 to M and its coordination with S phase events. Whether these functions contribute to prevention of centrosome amplification is being investigated. However, potential mechanisms can be proposed based on known protein associations with Gadd45a, as well as proteins that regulate Gadd45a transcription and are also required for efficient coordination of centrosome duplication and DNA synthesis.

Animals↗
PubMed1996

Induction of genomic instability in normal human bronchial epithelial cells by 238Pu alpha-particles.

Pulmonary deposition of alpha-particle-emitting radon daughters is estimated to account for 10% of all lung cancer deaths in the USA. However, the nature and timing of early (preneoplastic) genetic alterations in radon-associated lung cancer are still relatively uncertain. The purpose of this investigation was to determine whether genomic instability occurs after exposure of cultured normal human bronchial epithelial cells to six equal, fractionated doses of alpha-particles (total doses 2-4 Gy). Two weeks after the final exposure, foci of phenotypically altered cells (PACs) were detected in 0, 63 and 77% of control, low and high dose cultures respectively. Of these, 18% exhibited extended life spans relative to unexposed controls. Elevated frequencies of binucleated cells (BNCs), a marker of genomic instability, were observed in 60 and 38% of the PAC cultures from the low and high dose groups respectively. The micronucleus assay also showed evidence of genomic instability in 40 and 38% of PAC cultures from the low dose and high dose groups respectively. No changes in microsatellite length, another marker of genomic instability, were detected in any of the PAC samples with the 28 markers used for this assay. However, one PAC (L2) showed a hemizygous deletion at 9p13.3. Another PAC (H9), which exhibited the highest frequency of cells containing micronuclei (MN), exhibited a hemizygous deletion at 7q31.3. Each loss may represent a stable mutation that resulted either directly from irradiation or later in progeny of exposed cells because of alpha-particle-induced genomic instability. The fact that elevated levels of BNCs and MN were present in the progeny many generations after irradiation indicates that the genetic alterations detected with these two markers were not a direct consequence of radiation exposure, but of resulting genomic instability, which may be an early change after exposure to alpha-particles.

Adolescent↗
PubMed2000

Genomic instability and colorectal cancer.

Colon cancer results from the accumulation of genetic alterations. Genomic instability creates a permissive state in which a potential cancer cell is allowed to acquire enough mutations to become a cancer cell. Several forms of genomic instability are common in colon cancer: microsatellite instability (MSI), chromosome instability (CIN), and chromosome translocations. MSI occurs in approximately 15% of colon cancers and results from inactivation of the mutation mismatch repair (MMR) system secondary to either MMR gene mutations or hypermethylation of the hMLH1 promoter. It promotes tumorigenesis by generating mutations in target genes that possess coding microsatellite repeats, such as the transforming growth factor-beta receptor type II gene. CIN occurs in most other colon cancers and leads to a different pattern of gene alterations that culminate in tumor formation. It seems to result from mutations in genes that control mitosis, DNA damage repair, centrosome structure and function, and other fundamental processes in DNA replication. The clinical significance of genomic instability is now under investigation, and it is hoped that this research will soon yield results that have an immediate effect on the treatment of colon cancer.

Journal Article↗
PubMedDate not supplied

The role of genomic instability in human carcinogenesis.

Neoplastic cells typically possess numerous genomic lesions, which may include sequence alterations (point mutations, small deletions, and insertions) and/or gross structural abnormalities in one or more chromosomes (large-scale deletions, rearrangements, gene amplifications). Based upon this general observation, it has been suggested that cancer cells are genetically unstable, and that acquisition of genomic instability may represent an early step in the process of carcinogenesis and a general feature of many human tumors. Numerous studies have appeared that characterize the nature and frequency of occurrence of various molecular lesions in human tumors, and significant progress has been made towards the elucidation of the molecular mechanisms that govern genetic stability in normal cells and genetic instability in neoplastic cells. In this review, we examine the evidence that genomic instability plays a significant role in the genesis of various human tumors. Furthermore, we consider the possible molecular pathways to tumorigenesis in humans and how different forms of genetic instability may impact upon these pathways.

Cell Transformation, Neoplastic↗
PubMed2006

Decoupling of normal CD40/interleukin-4 immunoglobulin heavy chain switch signal leads to genomic instability in SGH-MM5 and RPMI 8226 multiple myeloma cell lines.

The processes mediating genomic instability and clonal evolution are obscure in multiple myeloma (MM). Acquisition of new chromosomal translocations into the switch region of the immunoglobulin heavy chain (IgH) gene (chromosome 14q32) in MM, often heralds transformation to more aggressive disease. Since the combined effects of CD40 plus interleukin-4 (IL-4) mediate IgH isotype class switch recombination (CSR), and this process involves DNA double strand break repair (DSBR), we hypothesized that CD40 and/or IL-4 activation of MM cells could induce abnormal DNA DSBR and lead to genomic instability and clonal evolution. In this study, we show that MM cell lines that are optimally triggered via CD40 and/or IL-4 demonstrate abnormal decoupling of IL-4 signal transduction from CD40. Specifically, CD40 alone was sufficient to trigger maximal growth of tumor cells. We further demonstrate that CD40 triggering induced both DNA DSBs as well as newly acquired karyotypic abnormalities in MM cell lines. Importantly, these observations were accompanied by induction of activation induced cytidine deaminase expression, but not gross apoptosis. These data support the role of abnormal CD40 signal transduction in mediating genomic instability, suggesting a role for the CD40 pathway and intermediates in myelomagenesis and clonal evolution in vivo.

CD40 Antigens↗
PubMed1998

Genomic instability and tumorigenic induction in immortalized human bronchial epithelial cells by heavy ions.

Carcinogenesis is postulated to be a progressive multistage process characterized by an increase in genomic instability and clonal selection with each mutational event endowing a selective growth advantage. Genomic instability as manifested by the amplification of specific gene fragments is common among tumor and transformed cells. In the present study, immortalized human bronchial (BEP2D) cells were irradiated with graded doses of either 1GeV/nucleon 56Fe ions or 150 keV/micrometer alpha particles. Transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Tumorigenic cells showed neither ras mutations nor deletion in the p16 tumor suppressor gene. In contrast, they harbored mutations in the p53 gene and over-expressed cyclin D1. Genomic instability among transformed cells at various stage of the carcinogenic process was examined based on frequencies of PALA resistance. Incidence of genomic instability was highest among established tumor cell lines relative to transformed, non-tumorigenic and control cell lines. Treatment of BEP2D cells with a 4 mM dose of the aminothiol WR-1065 significantly reduced their neoplastic transforming response to 56Fe particles. This model provides an opportunity to study the cellular and molecular mechanisms involved in malignant transformation of human epithelial cells by heavy ions.

Alpha Particles↗
PubMed2003

Genomic instability in human osteoblast cells after exposure to depleted uranium: delayed lethality and micronuclei formation.

It is known that radiation can induce a transmissible persistent destabilization of the genome. We have established an in vitro cellular model using HOS cells to investigate whether genomic instability plays a role in depleted uranium (DU)-induced effects. Transmissible genomic instability, manifested in the progeny of cells exposed to ionizing radiation, has been characterized by de novo chromosomal aberrations, gene mutations, and an enhanced death rate. Cell lethality and micronuclei formation were measured at various times after exposure to DU, Ni, or gamma radiation. Following a prompt, concentration-dependent acute response for both endpoints, there was de novo genomic instability in progeny cells. Delayed reproductive death was observed for many generations (36 days, 30 population doublings) following exposure to DU, Ni, or gamma radiation. While DU stimulated delayed production of micronuclei up to 36 days after exposure, levels in cells exposed to gamma-radiation or Ni returned to normal after 12 days. There was also a persistent increase in micronuclei in all clones isolated from cells that had been exposed to nontoxic concentrations of DU. While clones isolated from gamma-irradiated cells (at doses equitoxic to metal exposure) generally demonstrated an increase in micronuclei, most clonal progeny of Ni-exposed cells did not. These studies demonstrate that DU exposure in vitro results in genomic instability manifested as delayed reproductive death and micronuclei formation.

Cell Culture Techniques↗