DOCSLIB.ORG

(NBS) with Neurological Abnormalities and Without Chromosomal Instability

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(NBS) with Neurological Abnormalities and Without Chromosomal Instability Downloaded from jmg.bmjjournals.com on 9 March 2006 Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability E Seemanová, K Sperling, H Neitzel, R Varon, J Hadac, O Butova, E Schröck, P Seeman and M Digweed J. Med. Genet. 2006;43;218-224; originally published online 20 Jul 2005; doi:10.1136/jmg.2005.035287 Updated information and services can be found at: http://jmg.bmjjournals.com/cgi/content/full/43/3/218 These include: References This article cites 29 articles, 7 of which can be accessed free at: http://jmg.bmjjournals.com/cgi/content/full/43/3/218#BIBL Rapid responses You can respond to this article at: http://jmg.bmjjournals.com/cgi/eletter-submit/43/3/218 Email alerting Receive free email alerts when new articles cite this article - sign up in the box at the service top right corner of the article Topic collections Articles on similar topics can be found in the following collections Genetics (3709 articles) Notes To order reprints of this article go to: http://www.bmjjournals.com/cgi/reprintform To subscribe to Journal of Medical Genetics go to: http://www.bmjjournals.com/subscriptions/ Downloaded from jmg.bmjjournals.com on 9 March 2006 218 ORIGINAL ARTICLE Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability E Seemanova´, K Sperling, H Neitzel, R Varon, J Hadac, O Butova, E Schro¨ck, P Seeman, M Digweed ............................................................................................................................... J Med Genet 2006;43:218–224. doi: 10.1136/jmg.2005.035287 Background: Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder with hypersensitivity to ionising radiation. The clinical phenotype is characterised by congenital microcephaly, mild dysmorphic facial appearance, growth retardation, immunodeficiency, and greatly See end of article for increased risk for lymphoreticular malignancy. Most NBS patients are of Slavic origin and homozygous for authors’ affiliations the founder mutation 657del5. The frequency of 657del5 heterozygotes in the Czech population is 1:150. ....................... Recently, another NBS1 mutation, 643C.T(R215W), with uncertain pathogenicity was found to have Correspondence to: higher frequency among tumour patients of Slavic origin than in controls. This alteration results in the Professor M Digweed, substitution of the basic amino acid arginine with the non-polar tryptophan and thus could potentially Institute of Human interfere with the function of the NBS1 protein, nibrin. Genetics, Charite´- Universita¨tsmedizin Berlin, Methods and Results: Children with congenital microcephaly are routinely tested for the 657del5 mutation Augustenburger Platz 1, in the Czech and Slovak Republics. Here, we describe for the first time a severe form of NBS without 13353 Berlin, Germany; chromosomal instability in monozygotic twin brothers with profound congenital microcephaly and martin.digweed@charite. developmental delay who are compound heterozygotes for the 657del5 and 643C.T(R215W) NBS1 de mutations. Both children showed reduced expression of full length nibrin when compared with a control Revised version received and a heterozygote for the 657del5 mutation. Radiation response processes such as phosphorylation of 19 July 2005 ATM and phosphorylation/stabilisation of p53, which are promoted by NBS1, are strongly reduced in Accepted for publication cells from these patients. 20 July 2005 Published Online First Conclusions: Interestingly, the patients are more severely affected than classical NBS patients. 20 July 2005 Consequently, we postulate that homozygosity for the 643C.T(R215W) mutation will also lead to a, ....................... possibly very, severe disease phenotype. ijmegen breakage syndrome (NBS) is an autosomal heterozygosity, 657del5/643C.T(R215W), of the twin recessive chromosomal instability disorder charac- brothers is the primary cause of their clinical phenotype Nterised by congenital microcephaly, growth retarda- which seems to be more severe than the classical form of tion with pre- or postnatal onset, immunodeficiency, NBS. hyperradiosensitivity, and cancer predisposition.12 Most NBS patients are of Slavic origin and are homozygous for Clinical report 2–4 the founder NBS1 mutation 657del5. Congenital micro- The propositi, monozygotic twin boys (JR and PR), were born 2 cephaly is a hallmark of NBS and could be used, together to a 27 year old primigravid mother and a 29 year old father. with the identification of the responsible NBS1 mutations, as The couple is healthy, non-consanguineous, non-endogam- signal criteria for an early diagnosis of NBS in the Czech and eous, and had no contributory family history. Slovak Republics. Recently, we showed that the proportion of The pregnancy was uncomplicated until the 31st+1 week NBS patients among Czech infants with congenital micro- of gestation when fetal ultrasound examination showed an cephaly was 13%. In the Slovak Republic, this incidence was abnormal head shape and growth retardation of both fetuses. found to be as high as 50% among infants with both Two weeks later oligohydramnion occurred in one of the microcephaly and increased chromosomal instability.56 twins after amniotic fluid disruption; the next day both Among infants with primary microcephaly, screened for the children were spontaneously delivered head first. 657del5 mutation, we diagnosed monozygotic twin brothers Twin A, a boy (PR; fig 1A), was born after 33+1 weeks at the age of 2 months to be heterozygous for this mutation. gestation with an Apgar score of 7-9-9. His birth weight was The severe congenital microcephaly and hypotrophy were 1520 g, length was 40 cm, and OFC was 26 cm. Immediately indications for further analysis of the NBS1 gene. Another after birth, an abnormal skull shape with a small anterior NBS1 mutation, namely 643C.T(R215W), was detected on fontanel (0.560.5 cm), without a small fontanel, and with the second allele of the twin brothers. This mutation has been synostosis of coronal and sagittal sutures, was noted. The previously described in patients with acute lymphoblastic sutura metopica was prominent, occiput was flat, and the leukaemia,7 non-Hodgkin’s lymphoma,8 and at a high skull developed a microturricephalic shape. Ultrasound frequency among tumour patients of Slavic origin.9 Further investigation after birth showed enlarged, mild asymmetric clinical investigations of the children revealed partial lateral ventriculus, enlarged subarachnoidal areas (4 mm), lissencephaly and epileptic seizures, and respiratory and feeding problems were also noted. Based on the clinical Abbreviations: IR, irradiation; LCL, lymphoblastoid cell line; NBS, and molecular findings, we propose that the compound Nijmegen breakage syndrome; SKY, spectral karyotyping www.jmedgenet.com Downloaded from jmg.bmjjournals.com on 9 March 2006 Nijmegen breakage syndrome 219 and poor gyrification of the brain. No signs of intraventricular METHODS bleeding were found. Phototherapy was applied at 5 days Mutation analysis because of icterus. Enteral feeding was administered for the DNA was isolated from peripheral blood and lymphoblastoid first 5 days, but after that the child was breast fed and could cell lines (LCLs) were established according to standard be discharged home at the age of 33 days with 2095 g weight, procedures. Informed consent was obtained from the parents 43 cm length, and OFC 29.8 cm (all parameters below the of the children analysed in this study. Because of their third percentile, OFC very low, corresponding to 3 s). PR congenital microcephaly and Slavic origin, both children showed mild muscle hypertonia and brisk reflexes particu- were tested for the NBS1 mutation 657del5 at the age of larly involving the legs. A first attack of myoclonic seizures 2 months. The mutation analysis was carried out as was documented at the age of 3 months and progression to previously described5 and it was found that both children status epilepticus at 5 months was rapid. During his stay in were heterozygous for the Slavic mutation. In an attempt to the neurology clinic, he received medication for the status find a second mutation, further analysis of the NBS1 gene epilepticus and improved, but some 15 seizures per day were was carried out. The DNA samples were analysed by PCR common and feeding per sonda was necessary. Feeding and amplification and sequencing of NBS1 exons and flanking respiratory problems were progredient and therefore gastro- intronic sequences on an ABI 3100 DNA Analyzer (Applied stomy was necessary at the age of 7 months. Psychomotor Biosystems, Foster City, CA). development was severely retarded and correlated with development in infants in the first trimenon. OFC at the Western blot analysis age of 1 year was 37.6 cm, weight was 8750 g, and length Proteins were isolated from LCLs of both patients according was 69 cm (third percentile except for OFC, which corre- to standard procedures and examined in comparison with sponded to 25 SD). The child was last seen at the age of control cells and cells heterozygous for the 657del5 or 15 months and his somatic development due to feeding by 643C.T(R215W) mutation. Blots were probed with a rabbit gastrostomy and despite rare respiratory problems was polyclonal antibody (Novus Biologicals, Littleton, CO) direc- satisfactory (9500 g weight, 74 cm length, OFC 39 cm). His ted against the C-terminal portion of nibrin. Antibodies microturricephaly with prominent
Load more

Recommended publications
  • Epigenome Chaos: Stochastic and Deterministic DNA Methylation Events Drive Cancer Evolution
    cancers Review Epigenome Chaos: Stochastic and Deterministic DNA Methylation Events Drive Cancer Evolution Giusi Russo 1, Alfonso Tramontano 2, Ilaria Iodice 1, Lorenzo Chiariotti 1 and Antonio Pezone 1,* 1 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli “Federico II”, 80131 Naples, Italy; [email protected] (G.R.); [email protected] (I.I.); [email protected] (L.C.) 2 Department of Precision Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +39-081-746-3614 Simple Summary: Cancer is a group of diseases characterized by abnormal cell growth with a high potential to invade other tissues. Genetic abnormalities and epigenetic alterations found in tumors can be due to high levels of DNA damage and repair. These can be transmitted to daughter cells, which assuming other alterations as well, will generate heterogeneous and complex populations. Deciphering this complexity represents a central point for understanding the molecular mechanisms of cancer and its therapy. Here, we summarize the genomic and epigenomic events that occur in cancer and discuss novel approaches to analyze the epigenetic complexity of cancer cell populations. Abstract: Cancer evolution is associated with genomic instability and epigenetic alterations, which contribute to the inter and intra tumor heterogeneity, making genetic markers not accurate to monitor tumor evolution. Epigenetic changes, aberrant DNA methylation and modifications of chromatin proteins, determine the “epigenome chaos”, which means that the changes of epigenetic traits are Citation: Russo, G.; Tramontano, A.; randomly generated, but strongly selected by deterministic events.
    [Show full text]
  • The P53/P73 - P21cip1 Tumor Suppressor Axis Guards Against Chromosomal Instability by Restraining CDK1 in Human Cancer Cells
    Oncogene (2021) 40:436–451 https://doi.org/10.1038/s41388-020-01524-4 ARTICLE The p53/p73 - p21CIP1 tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells 1 1 2 1 2 Ann-Kathrin Schmidt ● Karoline Pudelko ● Jan-Eric Boekenkamp ● Katharina Berger ● Maik Kschischo ● Holger Bastians 1 Received: 2 July 2020 / Revised: 2 October 2020 / Accepted: 13 October 2020 / Published online: 9 November 2020 © The Author(s) 2020. This article is published with open access Abstract Whole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes, and W-CIN. CDKN1A, encoding for the CDK inhibitor p21CIP1, represents a critical target gene of p53/p73. Loss of p21CIP1 unleashes CDK1 activity which causes W-CIN in otherwise chromosomally stable cancer cells. fi Vice versa 1234567890();,: 1234567890();,: Consequently, induction of CDK1 is suf cient to induce abnormal microtubule assembly rates and W-CIN. , partial inhibition of CDK1 activity in chromosomally unstable cancer cells corrects abnormal microtubule behavior and suppresses W-CIN. Thus, our study shows that the p53/p73 - p21CIP1 tumor suppressor axis, whose loss is associated with W-CIN in human cancer, safeguards against chromosome missegregation and aneuploidy by preventing abnormally increased CDK1 activity.
    [Show full text]
  • Chromosome Instability Is Common in Human Cleavage-Stage Embryos
    TECHNICAL REPORTS Chromosome instability is common in human cleavage-stage embryos Evelyne Vanneste1,2,9, Thierry Voet1,9,Ce´dric Le Caignec1,3,4, Miche`le Ampe5, Peter Konings6, Cindy Melotte1, Sophie Debrock2, Mustapha Amyere7, Miikka Vikkula7, Frans Schuit8, Jean-Pierre Fryns1, Geert Verbeke5, Thomas D’Hooghe2, Yves Moreau6 & Joris R Vermeesch1 Chromosome instability is a hallmark of tumorigenesis. This combination, the approaches increase the accuracy of copy number study establishes that chromosome instability is also common variation (CNV) detection. We applied this technique to analyze the during early human embryogenesis. A new array-based method genomic constitution of all available blastomeres from 23 good-quality allowed screening of genome-wide copy number and loss of embryos from young women (o35 years old) without preimplanta- heterozygosity in single cells. This revealed not only mosaicism tion genetic aneuploidy screening indications undergoing IVF for for whole-chromosome aneuploidies and uniparental disomies genetic risks not related to fertility (Supplementary Table 1 online). in most cleavage-stage embryos but also frequent segmental This analysis unexpectedly revealed a high frequency of chromosome deletions, duplications and amplifications that were reciprocal instability in cleavage-stage embryos involving complex patterns of in sister blastomeres, implying the occurrence of breakage- segmental chromosomal imbalances and mosaicism for whole fusion-bridge cycles. This explains the low human fecundity chromosomes and uniparental isodisomies. These patterns are remini- and identifies post-zygotic chromosome instability as a leading scent of the chromosomal instabilities observed in human cancers1 cause of constitutional chromosomal disorders. and correspond with the complex chromosomal aberrations observed in individuals with birth defects13–15.
    [Show full text]
  • Centrosomes, Chromosome Instability (CIN) and Aneuploidy
    Available online at www.sciencedirect.com Centrosomes, chromosome instability (CIN) and aneuploidy Benjamin D Vitre and Don W Cleveland Each time a cell divides its chromosome content must be involved in microtubule nucleation, including the equally segregated into the two daughter cells. This critical g-tubulin ring complex and pericentrin [2,3]. process is mediated by a complex microtubule based Similar to the chromosomes, the centrosome at each apparatus, the mitotic spindle. In most animal cells the spindle pole is delivered into the corresponding daughter centrosomes contribute to the formation and the proper cell at cell division and then is duplicated in the following function of the mitotic spindle by anchoring and nucleating S phase. Each centriole pair so produced is used to microtubules and by establishing its functional bipolar nucleate microtubules to form a spindle pole in the next organization. Aberrant expression of proteins involved in centrosome biogenesis can drive centrosome dysfunction or mitosis. Despite their similar overall organization, the two abnormal centrosome number, leading ultimately to improper centrioles in each centrosome are not equivalent, with a mitotic spindle formation and chromosome missegregation. mother centriole that is one cell cycle older (and charac- Here we review recent work focusing on the importance of the terized, in mammals, by the presence of distal and sub- centrosome for mitotic spindle formation and the relation distal appendages involved in microtubule anchoring) between the centrosome status and the mechanisms and a more newly born daughter centriole [4]. controlling faithful chromosome inheritance. The centrosome duplication cycle and the cell cycle share common key regulators.
    [Show full text]
  • Nijmegen Breakage Syndrome: Case Report and Review of Literature
    Open Access Case report Nijmegen breakage syndrome: case report and review of literature Brahim El Hasbaoui1,&, Abdelhkim Elyajouri1, Rachid Abilkassem1, Aomar Agadr1 1Department of Pediatrics, Military Teaching Hospital Mohammed V, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat, Morocco &Corresponding author: Brahim El Hasbaoui, Department of Pediatrics, Military Teaching Hospital Mohammed V, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat, Morocco Key words: Nijmegen breakage syndrome, chromosome instability, immunodeficiency, lymphoma Received: 02 Jan 2018 - Accepted: 29 Jun 2019 - Published: 20 Mar 2020 Abstract Nijmegen Breakage Syndrome (NBS) is a rare autosomalrecessive DNA repair disorder characterized by genomic instability andincreased risk of haematopoietic malignancies observed in morethan 40% of the patients by the time they are 20 years old. The underlying gene, NBS1, is located on human chromosome 8q21 and codes for a protein product termed nibrin, Nbs1 or p95. Over 90% of patients are homozygous for a founder mutation: a deletion of five base pairs which leads to a frame shift and protein truncation. Nibrin (NBN) plays an important role in the DNA damage response (DDR) and DNA repair. DDR is a crucial signalling pathway in apoptosis and senescence. Cardinal symptoms of Nijmegen breakage syndrome are characteristic: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sino- pulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The diagnosis of NBS is initially based on clinical manifestations and is confirmed by genetic analysis.
    [Show full text]
  • Chromosomal Instability Versus Aneuploidy in Cancer
    Opinion Difference Makers: Chromosomal Instability versus Aneuploidy in Cancer 1,2 1,2,3, Richard H. van Jaarsveld and Geert J.P.L. Kops * Human cancers harbor great numbers of genomic alterations. One of the most Trends common alterations is aneuploidy, an imbalance at the chromosome level. The majority of human tumors are Some aneuploid cancer cell populations show varying chromosome copy num- aneuploid and tumor cell populations undergo karyotype changes over time ber alterations over time, a phenotype known as ‘chromosomal instability’ (CIN). in vitro. An elevated rate of chromo- Chromosome segregation errors in mitosis are the most common cause for CIN some segregation errors [known as in vitro, and these are also thought to underlie the aneuploidies seen in clinical ‘chromosomal instability (CIN)’] is believed to underlie this. cancer samples. However, CIN and aneuploidy are different traits and they are likely to have distinct impacts on tumor evolution and clinical tumor behavior. In Besides ongoing mitotic errors, evolu- this opinion article, we discuss these differences and describe scenarios in tionary dynamics also impact on the karyotypic divergence in tumors. CIN which distinguishing them can be clinically relevant. can therefore not be inferred from kar- yotype measurement (e.g., in aneu- Aneuploidy and Chromosomal Instability in Cancer ploid tumors). The development of neoplastic lesions is accompanied by the accumulation of genomic CIN, aneuploidy, and karyotype diver- mutations [1]. Recent sequencing efforts greatly enhanced our understanding of cancer gence are three fundamentally different genomes and their evolution. These studies strongly suggest that elevated mutation rates traits, but are often equated in litera- combined with evolutionary dynamics ultimately ensure clonal expansion of tumor cells, giving ture, for example, to describe aneu- rise to heterogeneous tumors [2,3].
    [Show full text]
  • Nijmegen Breakage Syndrome (NBS) with Neurological Abnormalities and Without Chromosomal Instability
    JMG Online First, published on July 20, 2005 as 10.1136/jmg.2005.035287 J Med Genet: first published as 10.1136/jmg.2005.035287 on 20 July 2005. Downloaded from Nijmegen Breakage Syndrome (NBS) with neurological abnormalities and without chromosomal instability E Seemanová1, K Sperling2, H Neitzel2, R Varon2, J Hadac3, O Butova2, E Schröck4, P Seeman5, M Digweed2* 1 Department of Clinical Genetics, Institute of Biology and Medical Genetics, 2nd Medical School of Charles University, Prague, Czech Republic 2 Institute of Human Genetics, Charité - Universitätsmedizin Berlin, Germany 3 Department of Neurology, University Hospital Krc, Prague, Czech Republic 4 Institute of Clinical Genetics, Medical faculty, TU Dresden, Germany 5 Department of Child Neurology, DNA Laboratory, 2nd Medical School of Charles University, Prague, Czech Republic * To whom correspondence should be addressed: Prof. Dr. M. Digweed Institute of Human Genetics Charité - Universitätsmedizin Berlin Augustenburger Platz 1 13353 Berlin Germany Tel.: 0049 30 450 566 016 Fax: 0049 30 450 566 904 E-mail: [email protected] http://jmg.bmj.com/ Key words: NBS, 657del5/643C>T(R215W) mutations, nibrin-Trp215, congenital microcephaly, chromosomal instability syndromes on September 25, 2021 by guest. Protected copyright. 1 Copyright Article author (or their employer) 2005. Produced by BMJ Publishing Group Ltd under licence. J Med Genet: first published as 10.1136/jmg.2005.035287 on 20 July 2005. Downloaded from ABSTRACT Background: Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder with hypersensitivity to ionizing radiation. The clinical phenotype is characterized by congenital microcephaly, mild dysmorphic facial appearance, growth retardation, immunodeficiency, and a highly increased risk for lymphoreticular malignancy.
    [Show full text]
  • A Role for Chromosomal Instability in the Development of and Selection
    British Journal of Cancer (2001) 84(4), 489–492 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2000.1604, available online at http://www.idealibrary.com on http://www.bjcancer.com A role for chromosomal instability in the development of and selection for radioresistant cell variants CL Limoli1, JJ Corcoran2, R Jordan3, WF Morgan2 and JL Schwartz3 1Department of Radiation Oncology, University of California, San Francisco, CA 94103–0806, USA; 2Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; 3Department of Radiation Oncology, University of Washington, Seattle, WA 98195, USA Summary Chromosome instability is a common occurrence in tumour cells. We examined the hypothesis that the elevated rate of mutation formation in unstable cells can lead to the development of clones of cells that are resistant to the cancer therapy. To test this hypothesis, we compared chromosome instability to radiation sensitivity in 30 independently isolated clones of GM10115 human–hamster hybrid cells. There was a broader distribution of radiosensitivity and a higher mean SF2 in chromosomally unstable clones. Cytogenetic and DNA double-strand break rejoining assays suggest that sensitivity was a function of DNA repair efficiency. In the unstable population, the more radioresistant clones also had significantly lower plating efficiencies. These observations suggest that chromosome instability in GM10115 cells can lead to the development of cell variants that are more resistant to radiation. In addition, these results suggest that the process of chromosome breakage and recombination that accompanies chromosome instability might provide some selective pressure for more radioresistant variants. © 2001 Cancer Research Campaign http://www.bjcancer.com Keywords: chromosome instability; radioresistance; DNA repair; radiation therapy It is well established that there are wide variations in the inherent significantly increased by radiation exposure (Morgan et al, 1996).
    [Show full text]
  • Telomere Loss As a Mechanism for Chromosome Instability in Human Cancer
    Published OnlineFirst May 18, 2010; DOI: 10.1158/0008-5472.CAN-09-4357 Published OnlineFirst on May 18, 2010 as 10.1158/0008-5472.CAN-09-4357 Review Cancer Research Telomere Loss as a Mechanism for Chromosome Instability in Human Cancer John P. Murnane Abstract Cancer cells commonly have a high rate of telomere loss, even when expressing telomerase, contributing to chromosome instability and tumor cell progression. This review addresses the hypothesis that this high rate of telomere loss results from a combination of four factors. The first factor is an increase in the frequency of double-strand breaks (DSB) at fragile sites in cancer cells due to replication stress. The second factor is that telomeres are fragile sites. The third factor is that subtelomeric regions are highly sensitive to DSBs, so that DSBs near telomeres have an increased probability of resulting in chromosome instability. The fourth factor is that cancer cells may be deficient in chromosome healing, the de novo addition of telomeres to the sites of DSBs, a mechanism that prevents chromosome instability resulting from DSBs near telomeres. Understanding these factors and how they influence telomere loss will provide important insights into the mechanisms of chromosome instability and the development of novel approaches for anti-cancer therapy. Cancer Res; 70(11); 4255–9. ©2010 AACR. Human telomeres are composed of a TTAGGG repeat se- used to identify cells in the population that have lost the quence and associated proteins that together form a cap that marked telomere, either spontaneously or as a result of DSBs keeps the ends of chromosomes from appearing as double- induced by the I-SceI endonuclease.
    [Show full text]
  • We Have Shown That Telomere Instability Due to Excessive Shortening Is the Main Driving Force of Chromosome Aberrations During the Early Stages of Cell Transformation
    Telomeres and Cancer UMR3244 – Dynamics of Genetic Information Arturo Londoño-Vallejo Chef d'équipe [email protected] Tel: +33 1 56 24 66 11 Tumorigenesis is a multistep process in which chromosomal instability plays an important role. We have shown that telomere instability due to excessive shortening is the main driving force of chromosome aberrations during the early stages of cell transformation. Our work has shown that this chromosome instability is associated with genome-wide changes in the chromatin landscape, which are directly correlated with transcriptome changes mainly affecting the non coding genome, including microRNAs. We have discovered that the deregulation of microRNAs following chromosome instability is responsible for the acquisition of tumor related phenotypes and the induction of a metastable state of cell differentiation in which epithelial cells respond to a senescence microenvironment by engaging in transitions deemed to be important for different steps in the metastatic progression of carcinomas. During this process, transformed epithelial cells acquire stem cell characteristics with renewal capacity, become cell-autonomous tumour initiating cells and are endowed of mesenchymal differentiation potential. Our laboratory is interested in exploring the molecular mechanisms that drive the production of cancer stem cells and specifically in dissecting the microRNA/transcription factor circuitry that connects such differentiation metastability to tumour aggressiveness. Identifying key actors in this circuitry will open
    [Show full text]
  • Chromosomal Instability As a Driver of Tumor Heterogeneity and Evolution
    Downloaded from http://perspectivesinmedicine.cshlp.org/ at New York Genome Center on September 8, 2017 - Published by Cold Spring Harbor Laboratory Press Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution Samuel F. Bakhoum1,2 and Dan Avi Landau2,3,4 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 2Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065 3Division of Hematology and Medical Oncology and the Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York 10021 4Core member of the New York Genome Center, New York, New York 10013 Correspondence: [email protected]; [email protected] Large-scale, massively parallel sequencing of human cancer samples has revealed tremen- dous genetic heterogeneity within individual tumors. Indeed, tumors are composed of an admixture of diverse subpopulations—subclones—that vary in space and time. Here, we discuss a principal driver of clonal diversification in cancer known as chromosomal instability (CIN), which complements other modes of genetic diversification creating the multilayered genomic instability often seen in human cancer. Cancer cells have evolved to fine-tune chromosome missegregation rates to balance the acquisition of heterogeneity while preserving favorable genotypes, a dependence that can be exploited for a therapeutic benefit. We discuss how whole-genome doubling events accelerate clonal evolution in a subset of tumors by providing a viable path toward favorable near-triploid karyotypes and present evidence for CIN-induced clonal speciation that can overcome the dependence on truncal initiating events. ancer originates from a single cell that has order in which these mutations occur, and the Cacquired a number of central genetic lesions specific types of alterations required to produce allowing it to rescind normal multicellular de- a malignant tumor (Bozic et al.
    [Show full text]
  • Chromosomal Instability in Tumor Initiation and Development Duc-Hiep Bach1, Wei Zhang2, and Anil K
    Published OnlineFirst July 26, 2019; DOI: 10.1158/0008-5472.CAN-18-3235 Cancer Review Research Chromosomal Instability in Tumor Initiation and Development Duc-Hiep Bach1, Wei Zhang2, and Anil K. Sood1,3,4 Abstract Chromosomal instability (CIN) is one of the major forms of CIN is stable between precursor lesions, primary tumor, and genomic instability in various human cancers and is recognized metastases or if it evolves during these steps. In this review, we as a common hallmark of tumorigenesis and heterogeneity. describe the influence of CIN on the various steps in tumor However, some malignant tumors show a paucity of chromo- initiation and development. Given the recognized significant somal alterations, suggesting that tumor progression and evo- effects of CIN in cancer, CIN-targeted therapeutics could have a lution can occur in the absence of CIN. It is unclear whether major impact on improving clinical outcomes. Introduction Interplay of CIN, Aneuploidy, and Most cancer types have the presence of a population of Chromothripsis in Cancer cells with chromosomal instability (CIN; ref. 1). This hall- Although CIN, aneuploidy, and chromothripsis are intimately mark of cancer is suggested as a major modulator of tumor linked, there are fundamental differences between them, espe- adaptation and evolution in response to challenges arising cially with regard to their function in various stages of tumor from the tumor microenvironment such as metastasis or progression. therapeutic resistance (2). CIN, one of the major forms of genomic instability in various human cancers, is typically CIN versus aneuploidy in cancer associated with structural and numerical chromosomal Aneuploidy, one of the most common chromosomal altera- – changes over time in tumor tissues (3 5).
    [Show full text]