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PubMed2001

A yeast gene, MGS1, encoding a DNA-dependent AAA(+) ATPase is required to maintain genome stability.

Changes in DNA superhelicity during DNA replication are mediated primarily by the activities of DNA helicases and topoisomerases. If these activities are defective, the progression of the replication fork can be hindered or blocked, which can lead to double-strand breaks, elevated recombination in regions of repeated DNA, and genome instability. Hereditary diseases like Werner's and Bloom's Syndromes are caused by defects in DNA helicases, and these diseases are associated with genome instability and carcinogenesis in humans. Here we report a Saccharomyces cerevisiae gene, MGS1 (Maintenance of Genome Stability 1), which encodes a protein belonging to the AAA(+) class of ATPases, and whose central region is similar to Escherichia coli RuvB, a Holliday junction branch migration motor protein. The Mgs1 orthologues are highly conserved in prokaryotes and eukaryotes. The Mgs1 protein possesses DNA-dependent ATPase and single-strand DNA annealing activities. An mgs1 deletion mutant has an elevated rate of mitotic recombination, which causes genome instability. The mgs1 mutation is synergistic with a mutation in top3 (encoding topoisomerase III), and the double mutant exhibits severe growth defects and markedly increased genome instability. In contrast to the mgs1 mutation, a mutation in the sgs1 gene encoding a DNA helicase homologous to the Werner and Bloom helicases suppresses both the growth defect and the increased genome instability of the top3 mutant. Therefore, evolutionarily conserved Mgs1 may play a role together with RecQ family helicases and DNA topoisomerases in maintaining proper DNA topology, which is essential for genome stability.

Adenosine Triphosphatases↗
PubMed2005

beta-catenin expression, DNA ploidy and clinicopathological features in ovarian cancer: a study in 253 patients.

The CTNNB1 gene and its product beta-catenin, a regulator of the Wnt signalling pathway, is often mutated and deregulated in human malignancies. Down stream targets of the Wnt signalling pathway are linked to genomic instability. In this study, the impact of beta-catenin expression on genomic instability in ovarian carcinoma, as determined by DNA ploidy, was investigated. Expression of beta-catenin was examined by immunohistochemistry in 253 ovarian carcinomas. The results were related to genomic instability and clinicopathological features of the patients. Membrane associated staining of beta-catenin was detected in nearly all cases with no correlation to clinical parameters. Most of the samples also had cytoplasmic (84%), while only 13% had nuclear beta-catenin localisation. A significant association between beta-catenin expression (cytoplasmic and nuclear) and histological subtype and degree of differentiation was observed. Nuclear beta-catenin was almost exclusively present in endometroid carcinomas. 53% of all endometroid tumours were positive for nuclear beta-catenin expression (P<0.0001). Mucinous carcinomas had the highest degree of cytoplasmic beta-catenin expression (92%), followed by endometroid (92%), mixed (90%), serous (82%), unclassified adenocarcinomas (81%), carcinomas clear cell and (70%), (P=0.01). Tumours with differentiation grade 1 (16%) and 2 (24%) had higher nuclear beta-catenin expression than grade 3 and clear cell carcinomas (6%) (P=0.012). Better prognostic outcome was found for patients with nuclear beta-catenin localisation as compared to the cases without (P=0.027). In conclusion, the study showed no correlation between beta-catenin expression in ovarian carcinoma and FIGO stage and genomic instability as determined by DNA ploidy status. However, nuclear beta-catenin expression was strongly associated with endometroid histological subtype. Finally, in ovarian cancer, although beta-catenin staining seems to be of prognostic importance with respect to nuclear staining in univariate analysis, only DNA ploidy status, histological grade and FIGO staging were of independent prognostic significance in multivariate analysis.

Cytoskeletal Proteins↗
PubMed2005

Bloom syndrome ortholog HIM-6 maintains genomic stability in C. elegans.

Bloom syndrome is caused by mutation of the Bloom helicase (BLM), a member of the RecQ helicase family. Loss of BLM function results in genomic instability that causes a high incidence of cancer. It has been demonstrated that BLM is important for maintaining genomic stability by playing a role in DNA recombination and repair; however, the exact function of BLM is not clearly understood. To determine the mechanism by which BLM controls genomic stability in vivo, we examined the phenotypes caused by mutation of the C. elegans BLM helicase ortholog, HIM-6. We find that the loss of HIM-6 leads to genomic instability as evidenced by an increased number of genomic insertions and deletions, which results in visible random mutant phenotypes. In addition to the mutator phenotype, him-6 mutants have a low brood size, a high incidence of males, a shortened life span, and an increased amount of germ line apoptosis. Upon exposure to high temperature, him-6 mutants that are serially passed become sterile demonstrating a mortal germ line phenotype. Our data suggest a model in which loss of HIM-6 results in genomic instability due to an increased number of DNA lesions, which either cannot be repaired and/or are introduced by low fidelity recombination events. The increased level of genomic instability that leads to him-6(ok412) mutants having a shortened life span.

Animals↗
PubMed1989

Extremely large chromosomal deletions are intimately involved in genetic instability and genomic rearrangements in Streptomyces glaucescens.

Genetic instability in Streptomyces glaucescens characteristically involves the occurrence of gross genomic rearrangements including high-level sequence amplification and extensive deletion. We investigated the relationship of the unstable melC and strS loci and a 100 kb region of the chromosome which frequently gives rise to intense heterogeneous DNA amplification. Standard chromosome walking using a cosmid bank in conjunction with a "reverse-blot" procedure enabled us to construct a contiguous genomic BamHI map of the unstable region exceeding 900 kb. The unstable genes and the amplifiable region (AUD locus) are physically linked within a 600 kb segment of the chromosome. The previously characterized deletions which affect these loci are merely components of much larger deletions ranging from 270 to over 800 kb which are polar in nature, effecting the sequential loss of the strS and melC loci. The more extensive deletions terminate either adjacent to, or in the vicinity of DNA reiterations at the AUD locus. Additionally, a deletion junction fragment and the corresponding deletion ends were cloned and analysed at the sequence level.

Base Sequence↗
PubMed2004

Molecular biology of Werner syndrome.

Human RecQ helicases, including the Werner syndrome helicase, participate in maintaining the integrity of the genome by suppressing illegitimate recombination or by repair of local DNA structural damage. Deterioration or loss of RecQ helicase associated with aging or genetic disorder results in genomic instability in tissues and organs where certain RecQ helicases are needed to correct aberrant DNA during proliferation. Such genomic instability, if not corrected, causes increased apoptotic cell death that would result in reduction of cell numbers in some tissues, leading to the deterioration of tissues and organs, the phenotypes of aging. Besides being associated with aging, genomic instability increases the risk of the development of neoplasms, both benign and malignant. These neoplasms are produced if either a checkpoint system or apoptosis is not functioning appropriately. Malignant tumor cells would then be selected from the mixed population of neoplasms by acquiring phenotypes that permit rapid cell growth and a strong capability to maintain their genome, such as tumor cells having increased levels of RecQ helicase expression, as we have observed in various tumor cell lines. Further studies are needed to discover effective measures to control genomic instability and to manage malignant tumor cells.

Animals↗
PubMed2001

Telomere dynamics in myelodysplastic syndromes and acute leukemic transformation.

Myelodysplastic syndromes (MDS) are characterized by cytopenias in the blood and dysplastic features in the hematopoietic cells. Although the impact of cytogenetic abnormalities is considerable for prognosis, the exact genetic mechanism of MDS remains undetermined. In this study we assessed cytogenetic changes, microsatellite alterations, and telomere dynamics in order to obtain further insight into the pathogenesis of MDS. Thirty-three percentage of MDS patients and 60% of post-MDS acute leukemia (post-MDS AML) had de novo microsatellite changes. In the MDS phase, however, > 60% of patients showed reduction of telomere lengths without microsatellite changes, indicating that telomere reduction in most MDS patients does not seem to be directly linked to genome instability, or that reduction of telomere length does not induce microsatellite changes in the MDS phase. Some MDS patients had microsatellite changes without telomerase elevation, indicating that genome instability might accumulate during the disease progression in some MDS patients, and this condition (cellular senescence) may be related to ineffective hemopoiesis in MDS patients. In contrast, 40% of post-MDS AML patients had elevated telomerase activity with microsatellite changes, indicating that approximately 40% of patients with post-MDS AML patients had accumulation of genome instability resulting in elevated telomerase activity in an attempt to obtain genetic stability. However, the remaining MDS patients had microsatellite changes without telomerase up-regulation, suggesting that some MDS had genome instability even after leukemic transformation. Most MDS patients with elevated telomerase activity in the AML phase had elevated telomerase activity even in the MDS phase without apparent change in telomere length before and after leukemic transformation. These findings indicate that telomerase activity in the MDS phase may be independent of telomere length, although telomere shortening seems to be related to genomic instability, and this process may be linked to apoptosis of MDS cells.

Cell Transformation, Neoplastic↗
PubMed2004

Chromosomal and microsatellite instability in sporadic gastric cancer.

BACKGROUND: Gastric cancer can progress through two pathways of genomic instability: chromosomal (CIN) and microsatellite instability (MSI). It is hypothesized that these two pathways are not always independent and that some tumors show overlap between these two mechanisms. METHODS: A total of 98 sporadic gastric cancers were classified based on their MSI status, using microsatellite assay with BAT26. Evidence for CIN was investigated by identifying loss of heterozygosity (LOH) events on chromosome arms, 5q, 10p, 17p, 17q, and 18q, which are regions harboring tumor suppressor genes that are significant in gastric cancer development. RESULTS: Twelve tumors (12%) showed high-frequency MSI (MSI-H). Overall, 43 of the tumors (44%) had at least one LOH event, with most frequent chromosomal losses observed on 10p and 18q (30%, respectively), followed by 5q (21%), 17p (14%), and 17q (12%). Interestingly, overlap was observed between CIN and MSI pathways. Of 43 cancers with LOH events, four (9%) were also MSI-H. It was also found that 48% of cancers without MSI-H had no LOH events identified, comprising a subgroup of tumors that were not representative of either of these two pathways of genomic instability. CONCLUSION: These results suggest that molecular mechanisms of genomic instability are not necessarily independent and may not be fully defined by either the MSI or CIN pathways in sporadic gastric cancers.

Adult↗
PubMed2005

Genetic disruption of cytosine DNA methyltransferase enzymes induces chromosomal instability in human cancer cells.

DNA methyltransferase 1 (DNMT1)-deficient mice are tumor-prone, and this has been proposed to result from the induction of genomic instability. To address whether loss of DNMT1, or the related protein DNMT3b, results in genomic instability in human cancer cells, we used a near-diploid human colorectal cancer cell line, HCT116, in which one or both DNMT genes were disrupted by homologous recombination. Array-based comparative genomic hybridization analyses indicated that double, but not single, DNMT knock-out cells display two specific alterations in regional DNA copy number, suggesting that DNMT deficiency and genomic DNA hypomethylation are not associated with widespread genomic amplifications or deletions in human cancer cells. However, spectral karyotype analyses revealed that DNMT-deficient HCT116 cells are highly unstable with respect to large-scale chromosomal alterations; furthermore, this effect is characterized by a high degree of individual cell heterogeneity. The induction of chromosomal alterations in DNMT-deficient cells was evidenced both by aneuploidy and by large increases in the number of novel chromosomal translocations. Studies of double knock-out cells indicated that the generation of chromosomal alterations is spontaneous and persistent in vitro, meeting the formal definition of genomic instability. In summary, we show that DNMT deficiency in human cancer cells results in constitutive genomic instability manifested by chromosomal translocations.

Aneuploidy↗
PubMed2019

The 22q11 low copy repeats are characterized by unprecedented size and structural variability.

Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.

22q11 Deletion Syndrome↗
PubMed2003

Chromosomal instability in pancreatic ductal cells from patients with chronic pancreatitis and pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is a disease with high mortality for which chronic pancreatitis confers a markedly increased risk. We hypothesize that chromosome instability and genomic damage occur in pre-neoplastic pancreatic ductal epithelium, and that this damage may be related to oxidative stress. We used dual-color fluorescence in situ hybridization with centromere probes and locus-specific arm probes for chromosome arms 11q, 17p, and 18q to identify genomic instability in cultures of normal-appearing human pancreatic ductal epithelium from normal organ donor controls compared to patients with chronic pancreatitis or pancreatic adenocarcinoma. To examine early pancreatic tumorigenesis, we studied only normal-appearing pancreatic ductal cells adjacent to pancreatitis or carcinoma. We found that, compared to the finding in normal controls, chromosomal abnormalities are present in normal-appearing human pancreatic ductal epithelia obtained from patients with chronic pancreatitis or pancreatic adenocarcinoma. Furthermore, these chromosomal abnormalities could be induced in cultured pancreatic ductal epithelium from normal organ donors by chronic exposure to dilute hydrogen peroxide, suggesting that oxidative stress may contribute to the development of chromosomal instability in the pancreas. These results elucidate a potential mechanism linking chronic pancreatitis to pancreatic cancer and suggest that chromosomal instability may be an early event in the pathogenesis of pancreatic cancer.

Adenocarcinoma↗
PubMed2005

Array CGH technologies and their applications to cancer genomes.

Cancer is a disease characterized by genomic instability. Comparative genomic hybridization (CGH) is a technique designed for detecting segmental genomic alterations. Recent advances in array-based CGH technology have enabled examination of chromosomal regions in unprecedented detail, revolutionizing our understanding of tumour genomes. A number of array-based technologies have been developed, aiming to improve the resolution of CGH, enabling researchers to refine and define regions in the genome that may be causal to cancer, and facilitating gene discovery at a rapid rate. This article reviews the various array CGH platforms and their use in the study of cancer genomes. In addition, the need for high-resolution analysis is discussed as well as the importance of studying early-stage disease to discover genetic alterations that may be causal to cancer progression and aetiology.

Chromosomes, Human↗
PubMedDate not supplied

Hepatitis viruses and hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is among the most frequent malignancies worldwide. Hepatitis viruses, such as the hepatitis B virus (HBV) and hepatitis C virus (HCV) are undoubtedly listed in the etiology of HCC. Studies show that, in the near future, viral hepatitis will carry increasing weight in the etiology of HCC. This review briefly discusses the known carcinogenic effects of HBV and HCV in the light of experimental and human studies. The data show that viral proteins may directly interfere with gene products responsible for cell proliferation and cell growth. Many other signal transduction cascades may be affected as well. Direct integration of HBV viral sequences into the host genome increases the genomic instability. The genomic imbalance allows the development and survival of malignant clones bearing defected genomic information. HBV and HCV infection induces indirect and direct mechanisms through cellular damage, increased regeneration and cell proliferation, therefore enhancing the development of HCC.

Hepatitis B↗
PubMedDate not supplied

Microsatellite alterations and K-ras, TGFbetaRII, IGFRII and bax mutations in sporadic cancers of the gastrointestinal tract.

DNA was analyzed from 57 sporadic gastrointestinal tumors (34 pancreatic cancers, 23 colon tumors) and cognate normal tissues to verify whether mutations at coding sequences were associated with microsatellite instability (MSI). Genomic instability was present in 41% (14/34) of pancreatic samples and in 26% (6/23) of colon cancers previously tested by six microsatellite markers. The tumors included 37 cases showing no MSI; 15 cases with MSI at only 1 locus and 5 cases with MSI at 2 or more loci. All the samples were screened for mutations in genes containing repeated tracts in their coding sequences (TGFbetaRII, IGFRII and bax) and in codon 12 of the K-ras oncogene. Furthermore, loss of heterozygosity (LOH) at NM23.H1 locus was tested, 17/34 (50%) pancreatic tumors and 6/23 (26%) colon cancers showed mutations in codon 12 of K-ras; allelic loss of NM23. H1 locus was found in 6/18 (33%) informative colon tumors and in no pancreatic cancers. The TGFbetaRII, IGFRII and bax genes were altered in 3 (13%), 1 (4%) and 3 (13%) out of 23 colon tumors respectively, but no mutation was detected in pancreatic cancers. Mutations in the repeated nucleotide stretches within the coding sequences of TGFbetaRII, IGFRII and bax genes were found only in colon tumors with a high unstable phenotype (more than 3 microsatellite loci altered).

Adult↗
PubMed2002

[Hepatitis viruses and hepatocarcinogenesis].

INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most frequent malignancies worldwide. Hepatitis viruses, as the hepatitis virus B (HBV) and hepatitis virus C (HCV), among other environmental factors, are undoubtedly listed in the etiology of HCC. Studies indicate that in the near future viral hepatitis will be of increasing importance in the etiology of HCC. AIM: This review briefly discusses the known carcinogenic effects of HBV and HCV in the light of experimental and human studies. RESULTS: Data show that viral proteins may directly interfere with gene products responsible for cell proliferation and cell growth, therefore this direct effect may influence the basic mechanism of the cell cycle. Many other signal transduction cascades may be affected as well. Direct integration of HBV viral sequences into the host genome increases the genomic instability. The genomic imbalance allows the development and survival of malignant clones bearing defected genomic information. CONCLUSION: HBV and HCV infection induce indirect and direct mechanisms through cellular damage, increased regeneration and cell proliferation, therefore enhancing the development of HCC.

Carcinoma, Hepatocellular↗
PubMed2005

Bladder cancer stage and outcome by array-based comparative genomic hybridization.

PURPOSE: Bladder carcinogenesis is believed to follow alternative pathways of disease progression driven by an accumulation of genetic alterations. The purpose of this study was to evaluate associations between measures of genomic instability and bladder cancer clinical phenotype. EXPERIMENTAL DESIGN: Genome-wide copy number profiles were obtained for 98 bladder tumors of diverse stages (29 pT(a), 14 pT1, 55 pT(2-4)) and grades (21 low-grade and 8 high-grade superficial tumors) by array-based comparative genomic hybridization (CGH). Each array contained 2,464 bacterial artificial chromosome and P1 clones, providing an average resolution of 1.5 Mb across the genome. A total of 54 muscle-invasive cases had follow-up information available. Overall outcome analysis was done for patients with muscle-invasive tumors having "good" (alive >2 years) versus "bad" (dead in <2 years) prognosis. RESULTS: Array CGH analysis showed significant increases in copy number alterations and genomic instability with increasing stage and with outcome. The fraction of genome altered (FGA) was significantly different between tumors of different stages (pT(a) versus pT1, P = 0.0003; pT(a) versus pT(2-4), P = 0.02; and pT1 versus pT(2-4), P = 0.03). Individual clones that differed significantly between different tumor stages were identified after adjustment for multiple comparisons (false discovery rate < 0.05). For muscle-invasive tumors, the FGA was associated with patient outcome (bad versus good prognosis patients, P = 0.002) and was identified as the only independent predictor of overall outcome based on a multivariate Cox proportional hazards method. Unsupervised hierarchical clustering separated "good" and "bad" prognosis muscle-invasive tumors into clusters that showed significant association with FGA and survival (Kaplan-Meier, P = 0.019). Supervised tumor classification (prediction analysis for microarrays) had a 71% classification success rate based on 102 unique clones. CONCLUSIONS: Array-based CGH identified quantitative and qualitative differences in DNA copy number alterations at high resolution according to tumor stage and grade. Fraction genome altered was associated with worse outcome in muscle-invasive tumors, independent of other clinicopathologic parameters. Measures of genomic instability add independent power to outcome prediction of bladder tumors.

Chromosome Mapping↗
PubMed1994

Development of surrogate endpoint biomarkers for clinical trials of cancer chemopreventive agents: relationships to fundamental properties of preinvasive (intraepithelial) neoplasia.

The tissue changes offering the greatest immediate potential for development as surrogate endpoint biomarkers (SEBs) to be used in Phase II trials of cancer chemopreventive agents are those derived from the microscopic tissue changes pathologists use to make the diagnosis of preinvasive (intraepithelial) neoplasia. These changes comprise four categories: proliferative index, ploidy, nuclear morphometry (size, shape, texture, and pleomorphism), and nucleolar morphometry (number, size, shape, position, and pleomorphism). Computer-assisted image analysis (CIA) permits dozens of additional morphometric parameters to be developed. Other categories of candidate SEBs are: DNA and chromosomal structural changes associated with genomic instability, activation of oncogenes and inactivation of tumor suppressor genes, structural changes in differentiated molecules, and aberrations of growth factor/receptor structure and function. Self-perpetuating DNA breakage with secondary mutator mutations in genomic stability genes is a major mechanism by which the genomic instability characteristic of neoplasia occurs, and from which stem other basic neoplastic properties, including clonal evolution, along multiple pathways of genetic variation that are stochastically determined, continuously increasing proliferation, rate and extent of phenotypic heterogeneity. SEBs resulting from genomic instability include homogeneously staining regions, double minute chromosomes, micronuclei, dicentrics, gene amplification, loss of heterozygosity, and alterations in chromosome number. Newly developed assays for detecting genomic instability include comparative genomic hybridization using fluorescence in situ hybridization on > 20 micron-thick sections monitored by confocal laser scanning microscopy, assays for microsatellite instability, and restriction landmark genomic scanning. These assays offer promise for detecting the earliest molecular changes of neoplasia in normal-appearing epithelium prior to the onset of the dysplastic phase of intraepithelial neoplasia.

Anticarcinogenic Agents↗
PubMed2006

DNA degradation at unprotected telomeres in yeast is regulated by the CDK1 (Cdc28/Clb) cell-cycle kinase.

In the absence of functional telomeric cap protection, the ends of eukaryotic chromosomes are subject to DNA damage responses that lead to cell-cycle arrest and, eventually, genomic instability. However, the controlling activities responsible for the initiation of genome instability on unprotected telomeres remained unclear. Here we show that in budding yeast, unprotected telomeres undergo a tightly cell-cycle-regulated DNA degradation. Ablation of the function of essential capping proteins Cdc13p or Stn1p only caused telomere degradation in G2/M, but not in G1 of the cell cycle. Accordingly, G1-arrested cells with unprotected telomeres remained viable, while G2/M-arrested cells failed to recover. The data also show that completion of S phase and the activity of the S-Cdk1 kinase were required for telomere degradation. These results strongly suggest that after a loss of the telomere capping function, telomere-led genome instability is caused by tightly regulated cellular DNA repair attempts.

CDC28 Protein Kinase, S cerevisiae↗
PubMed1997

High frequency of genetic instability of microsatellites in human prostatic adenocarcinoma.

In order to investigate the genomic instability associated with prostate cancer, 36 microsatellite marker loci on chromosomes 1p, 3p, 5q, 8p, 8q, 9p, 11q and 13q were analyzed using microdissected samples from prostate cancer and adjoining microscopically normal tissues from the same slide. DNA was extracted from the normal and tumor cells of 40 microdissected prostate-cancer samples, amplified by PCR, and analyzed for microsatellite instability (MSI) using 36 different polymorphic DNA markers. In the present study, we have utilized a highly refined technique of PCR product separation on a sequencing gel, developed in our laboratory, which clearly shows high-quality results for the microsatellite instability in prostate cancer. The results of this study suggest that 45% (18 out of 40) showed genomic instability at a minimum of 1 locus; 4 cases each showed MSI at one and 2 loci, 4 cases had MSI at 3 loci, 3 cases showed MSI at 5 loci, while one case each showed MSI at 7, 8 and 15 loci. There was no significant correlation between the MSI and stage or grade of the tumors. This extensive study on genomic instability in prostate cancer found the occurrence of MSI to be very high, which suggests a role of MSI in the pathophysiology of prostate cancer.

Adenocarcinoma↗