DOCSLIB.ORG

Formal Discussion Of: Somatic Mutations and Carcinogenesis'

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Formal Discussion Of: Somatic Mutations and Carcinogenesis' Formal Discussion of: Somatic Mutations and Carcinogenesis' HOWARD J. CURTIS Biology Department, Brookhaven National Laboratory, Upton, New York SUMMARY A great deal of evidence is now available indicating that mutations play a dominant role in the aging process. Because carcinogenesis is one facet of the aging process, mu tations must play a major role here also. However, carcinogenesis certainly does not consist of the simple induction of a mutation in one cell which confers the property of uncontrolled growth on that cell and its progeny. There must be some general condi tions, as well as a specific event, before carcinogenesis can take place. It is postulated that mutations in one form or another are responsible for both conditions. The mutation theory of carcinogenesis is old and well of the 1st generation (3). We then scored chromosome known to all workers in the field. It is an extremely aberrations in liver cells of mice by inducing cell division attractive theory, and there are many pieces of evidence by partial hepatectomy and examining anaphase figures which argue in its favor. Radiation, which is a very po (14). (Fig. 1). The percentage of cells containing aberra tent mutagenic agent, is also a very effective carcinogen. tions is taken as an index of the mutations present in these Most, if not all, of the chemical carcinogens are also muta cells. gens. The virus theory of carcinogenesis is well estab With the use of this technic a number of different situa lished in certain special cases, and in a very real sense it is tions have been investigated. First it was found that a facet of mutation theory. aberrations increase steadily with age (Chart 1). Next, On the other hand, there are many puzzling phenomena following a dose of X-radiation, there are a large increase which cause one to doubt this theory. For example, if in aberrations and a very slow return to normal (Chart 1). the theory is true, why does it take as long as 40 years It is known that chronic X- or ‘y-radiationis only about after a person receives a dose of radiation for a tumor to 25 % as effective in shortening the life-span as an acute appear? If a mutation to carcinogenicity is produced, dose of the same total size. It is found that the same is one would expect it to manifest itself very soon thereafter. true for the production of chromosome aberrations (Chart There is also the question of whether mutations, especially 2). It is also known that for neutron irradiation, chronic spontaneous mutations, can be produced in somatic cells. irradiation is just as effective in shortening the life-span A number of years ago it was noted that the life expec as acute irradiation. The same has been found for the tancies of animals exposed to ionizing radiation are short production of chromosome aberrations (8) (Chart 3). ened in proportion to the radiation dose received. It It is well known that some inbred strains of mice are appears that the animals die from the same diseases and quite short-lived and some quite long-lived. It was in about the same proportion as normal animals, but they found that chromosome aberrations increase quite rapidly contract the diseases sooner. In investigating this phe in one short-lived strain and quite slowly in a long-lived nomenon, it seemed that a very likely explanation would strain (4) (Chart 4). be that the radiation induced mutations in the somatic Thus in every situation tried so far there is a direct cells which caused a lack of efficiency and, thus, deteriora correlation between the degree of life shortening and the tion in organs whose cells are not capable of cell division development of somatic mutations. It should be kept in and cancer in organs whose cells regularly undergo mitosis. mind that irradiated animals die, to a very considerable In order to test this idea, it was necessary to develop a extent, from cancer, so that one can equally well say that method for estimating mutations in somatic cells. For this we made an analogy with plants, where, because factors which cause increased somatic mutations also quan somatic cells differentiate to form germ cells, chromosome titatively increase cancer production. aberrations in somatic cells can be related to true muta One of the problems raised by this work is the long de tions scored in the next generation. It was found that lay between cause and effect. Thus a dose of radiation the mutations scored in the 2nd generation are propor given to a young adult mouse may produce serious chro tional to chromosome aberrations scored in somatic cells mosomal damage in almost every cell in the body; yet the mouse appears unaffected and may not show signs of 1 The research reported in this paper was carried out at Brook havenNational Laboratoryunder the auspices ofthe U. S. Atomic aging until many months later. At first glance, this situa Energy Commission. tion seems to contradict the theory, but in the light of 1305 Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 1965 American Association for Cancer Research. 1306 Cancer Research Vol. 25, September 1965 I I @I I 70 - 0 92 rods NEUTRONS -SINGLE DOSE *31 rods NEUTRONS PER WEEK @ 0 X-RAY 100 - @260 - £ CONTROL I- :i 700r 4 50 - 0 2 40 - @ 30- @4O- ,,-‘ - @ - ., 20 - 10 - @ 2@ £T@TTIITTT DAYSFROMSTARTOF EXPERIMENT 8 9 0 IF 2 CHART 3.—Chromosome aberrations in liver cells of (a) mice AGE - MONTHS subjected to chronic neutron irradiation, (b) mice subjected to CHART 1.—Chromosome aberrations in liver cells as a function acute neutron irradiation, and (c) control mice. The dashed line of age in normal mice and in mice that had received a large dose of gives the rate of build-up of aberrations in Group a mice which X-rays. The curves show the steady increase in the number of would be expected if chronic irradiation were as effective in pro chromosome aberrations (mutations) with natural aging and the ducing aberrations as acute is, and it will be seen that the experi dramatic increase and slow return to normal following X-rays mental points fall closely on this line. The data show that there is no chromosomal healing following even small doses of neutrons [from Stevenson and Curtis (14)]. [from Curtis et at. (8)1. IIIIII •STRAIN A/HEJ 100 - 0STRAIN C57BL/6J U) 100 z (I)z YOUNG MICE 0 0 ————OLDBREEDERS I- 80 - ,fr—-—.---@ @ 80 w w , 60 - , @ 60 Ui 0 U) 0 40 - -@ —. ._o— —-0@ 0 U) 0 0 40 o—___o_•@__ 1' I 0 C) I 20 - C) 20 a! <@T@7TI I _0 100 200 300 400 500 600 700 AGE - DAYS 60 90 120 150 180 210 240 270 CHART4.—Chromosome aberrations in liver cells of normal mice AGE - DAYS of 2 different inbred strains as a function of age. The median life CHART 2.—Chromosome aberrations in liver cells of (a) mice span of each strain is indicated by the arrows. In each case the solid lines represent animals 8 weeks of age at the start of the ex subjected to chronic 7-irradiation, (b) mice given a single dose of periment, and the broken lines, old breeding animals about 1 year X-rays, (c) normal mice. The dashed line shows the rate of old at the start of the experiment [from Crowley and Curtis (4)]. build-up which would be expected for mice of Group a if chronic irradiation were as effective in producing chromosome aberrations (DNA)1 —ø'(RNA)1-—e@(Protein)1 as acute irradiation is. Since the experimental curve has a much smaller slope, it is concluded that chromosome healing takes place following small doses of radiation [from Curtis and Crowley (7)]. (DNA)2 —@(RNA)2 —@(Protein)2 modern theory of the role of the nucleus in cell function, (DNA)3 —@(RNA)3 —.@(Protein)3 it may actually strengthen it. A schematic representation of the control of cellular I I I @ function is given in Chart 5. It is believed that there is I I 1 DNA2 molecule of each species, 10—100RNA molecules (DNA)@—.@(RNA)@---.'@ (Protein)@ of each, and more than 1000 protein molecules of each. CHART5.—Schematic representation of the control of cell func Thus if a mutation occurs which destroys a single DNA tion. The chromosomes contain the different individual DNA molecule, the cell can still function for a long time on molecules, each of which synthesizes the corresponding RNA molecules, which in turn synthesize the corresponding proteins. 2 The abbreviations used are: DNA, deoxyribonucleic acid; A mutation can be considered as the elimination of 1 or more DNA RNA, ribonucleic acid. molecules, which eventually eliminates that molecular line. Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 1965 American Association for Cancer Research. CURTIS—Formal Discuss-ion of Somatic Mutations and Carcinogenesis 1307 (I) z 0 I- L.J 4 0 U) 0 0 I C) a! DAYS FROM START OF EXPERIMENT CHART6.—Chromosome aberrations in liver cells of both irradiated and control mice, and with and without carbon tetrachloride injections every 45 days (arrows) , which destroyed about half the liver. The standard error of each point is indicated. This induced mitosis caused a relatively slow return to control levels [from Curtis et al. (9)]. stored RNA and proteins. Indeed this seems to be the plant cells, and it now seems even more potent for animal case, and one can cite a number of instances in which cells.
Load more

Recommended publications
  • Genomic Profiling Reveals High Frequency of DNA Repair Genetic
    www.nature.com/scientificreports OPEN Genomic profling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer Reham Abdel‑Wahab1,9, Timothy A. Yap2, Russell Madison4, Shubham Pant1,2, Matthew Cooke4, Kai Wang4,5,7, Haitao Zhao8, Tanios Bekaii‑Saab6, Elif Karatas1, Lawrence N. Kwong3, Funda Meric‑Bernstam2, Mitesh Borad6 & Milind Javle1,10* DNA repair gene aberrations (GAs) occur in several cancers, may be prognostic and are actionable. We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (PD‑1), and its ligand (PD‑L1) expression. Comprehensive genomic profling (CGP) of 760 GBC was performed. We investigated GAs in 19 DNA repair genes including direct DNA repair genes (ATM, ATR , BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, and RAD50) and caretaker genes (BAP1, CDK12, MLL3, TP53, and BLM) and classifed patients into 3 groups based on TMB level: low (< 5.5 mutations/Mb), intermediate (5.5–19.5 mutations/Mb), and high (≥ 19.5 mutations/Mb). We assessed MSI status and PD‑1 & PD‑L1 expression. 658 (86.6%) had at least 1 actionable GA. Direct DNA repair gene GAs were identifed in 109 patients (14.2%), while 476 (62.6%) had GAs in caretaker genes. Both direct and caretaker DNA repair GAs were signifcantly associated with high TMB (P = 0.0005 and 0.0001, respectively). Tumor PD‑L1 expression was positive in 119 (15.6%), with 17 (2.2%) being moderate or high. DNA repair GAs are relatively frequent in GBC and associated with coexisting actionable mutations and a high TMB.
    [Show full text]
  • Intercellular Competition and the Inevitability of Multicellular Aging
    Intercellular competition and the inevitability of multicellular aging Paul Nelsona,1 and Joanna Masela aDepartment of Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ 85721 Edited by Raghavendra Gadagkar, Indian Institute of Science, Bangalore, India, and approved October 6, 2017 (received for review November 14, 2016) Current theories attribute aging to a failure of selection, due to Aging in multicellular organisms occurs at both the cellular either pleiotropic constraints or declining strength of selection and intercellular levels (17). Multicellular organisms, by definition, after the onset of reproduction. These theories implicitly leave require a high degree of intercellular cooperation to maintain open the possibility that if senescence-causing alleles could be homeostasis. Often, cellular traits required for producing a viable identified, or if antagonistic pleiotropy could be broken, the multicellular phenotype come at a steep cost to individual cells effects of aging might be ameliorated or delayed indefinitely. (14, 18, 19). Conversely, many mutant cells that do not invest in These theories are built on models of selection between multicel- holistic organismal fitness have a selective advantage over cells lular organisms, but a full understanding of aging also requires that do. If intercellular competition occurs, such “cheater” or examining the role of somatic selection within an organism. “defector” cells may proliferate and displace “cooperating” cells, Selection between somatic cells (i.e., intercellular competition) with detrimental consequences for the multicellular organism can delay aging by purging nonfunctioning cells. However, the (20, 21). Cancer, a leading cause of death in humans at rates that fitness of a multicellular organism depends not just on how increase with age, is one obvious manifestation of cheater pro- functional its individual cells are but also on how well cells work liferation (22–24).
    [Show full text]
  • Clonal Hematopoietic Mutations Linked to Platelet Traits and the Risk Of
    REVIEW ARTICLE Clonal hematopoietic mutations linked to Ferrata Storti Foundation platelet traits and the risk of thrombosis or bleeding Alicia Veninga, 1,* Ilaria De Simone, 1,* Johan W.M. Heemskerk, 1 Hugo ten Cate, 1,2,3 and Paola E.J. van der Meijden 1,2 1Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht; 2Thrombosis Expertise Center, Heart and Vascular Haematologica 2020 Center, Maastricht University Medical Center, Maastricht and 3Department of Internal Volume 105(8):2020-2031 Medicine, Maastricht University Medical Center, Maastricht, the Netherlands *AV and IDS contributed equally as co-first authors. ABSTRACT latelets are key elements in thrombosis, particularly in atherosclero - sis-associated arterial thrombosis (atherothrombosis), and hemosta - Psis. Megakaryocytes in the bone marrow, differentiated from hematopoietic stem cells are generally considered as a uniform source of platelets. However, recent insights into the causes of malignancies, includ - ing essential thrombocytosis, indicate that not only inherited but also somatic mutations in hematopoietic cells are linked to quantitative or qualitative platelet abnormalities. In particular cases, these form the basis of thrombo-hemorrhagic complications regularly observed in patient groups. This has led to the concept of clonal hematopoiesis of indetermi - nate potential (CHIP), defined as somatic mutations caused by clonal expansion of mutant hematopoietic cells without evident disease. This concept also provides clues regarding the importance of platelet function Correspondence: in relation to cardiovascular disease. In this summative review, we present an overview of genes associated with clonal hematopoiesis and altered P.E.J. VAN DER MEIJDEN platelet production and/or functionality, like mutations in JAK2 . We con - [email protected] sider how reported CHIP genes can influence the risk of cardiovascular disease, by exploring the consequences for platelet function related to Received: January 31, 2020.
    [Show full text]
  • Germline and Somatic Mosaicism in a Family with Multiple Endocrine
    2 180 H J B H Beijers and others Mosaicism in family with MEN1 180:2 K15–K19 Case Report syndrome Germline and somatic mosaicism in a family with multiple endocrine neoplasia type 1 (MEN1) syndrome Hanneke J B H Beijers1,2, Nike M L Stikkelbroeck2, Arjen R Mensenkamp3, Rolph Pfundt3, Rob B van der Luijt4, Henri J L M Timmers2, Ad R M M Hermus2 and Marlies J E Kempers3 Correspondence 1Department of Internal Medicine, Maasziekenhuis Pantein, Boxmeer, The Netherlands, 2Division of Endocrinology, should be addressed Department of Internal Medicine, 3Department of Human Genetics, Radboud University Nijmegen Medical Center, to M J E Kempers 4 Nijmegen, The Netherlands, and Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Email The Netherlands Marlies.Kempers@ radboudumc.nl Abstract Context: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1 and can be diagnosed based on clinical, familial and/or genetic criteria. We present a family in which we found both germline and somatic mosaicism for MEN1. Family description: In our proband, we diagnosed MEN1. The mutation was not detected in her parents (DNA extracted from leucocytes). When her brother was found to harbor the same MEN1 mutation as our proband and, around the same time, their father was diagnosed with a neuroendocrine carcinoma, this tumor was investigated for the MEN1 mutation as well. In the histologic biopsy of this tumor, the same MEN1 mutation was detected as previously found in his children. Re-analysis of his blood using multiplex ligation-dependent probe amplification (MLPA) showed a minimal, but consistently decreased signal for the MEN1-specific MLPA probes.
    [Show full text]
  • Evolution and Genomic Signatures of Spontaneous Somatic Mutation in Drosophila Intestinal Stem Cells
    Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Evolution and genomic signatures of spontaneous somatic mutation in Drosophila intestinal stem cells Nick Riddiford1, Katarzyna Siudeja1, Marius van den Beek1, Benjamin Boumard1, Allison J. Bardin1 * 1 Institut Curie, PSL Research University, CNRS UMR 3215, INSERM U934, Stem Cells and Tissue Homeostasis Group, Paris, France. * author for correspondence Abstract Spontaneous mutations can alter tissue dynamics and lead to cancer initiation. While large- scale sequencing projects have illuminated processes that influence somatic mutation and subsequent tumour evolution, the mutational dynamics operating in the very early stages of cancer development are currently not well understood. In order to explore mutational processes in the early stages of cancer evolution, we exploited neoplasia arising spontaneously in the Drosophila intestine. Analysing whole-genome sequencing data with a dedicated bioinformatic pipeline, we found neoplasia formation to be driven largely through the inactivation of Notch by structural variants, many of which involve highly complex genomic rearrangements. The genome-wide mutational burden in neoplasia was found to be similar to that of several human cancers. Finally, we identified genomic features associated with spontaneous mutation and defined the evolutionary dynamics and mutational landscape operating within intestinal neoplasia over the short lifespan of the adult fly. Our findings provide unique insight into mutational dynamics operating over a short time scale in the genetic model system, Drosophila melanogaster. 1 Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Introduction The accumulation of mutations in somatic tissues plays a major role in cancer and is proposed to contribute to ageing (Al Zouabi and Bardin 2020).
    [Show full text]
  • The Somatic Mutation Landscape of the Human Body
    bioRxiv preprint doi: https://doi.org/10.1101/668624; this version posted June 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. The somatic mutation landscape of the human body Pablo E. García-Nieto, Ashby J. Morrison, Hunter B. Fraser* Department of Biology, Stanford University, Stanford CA *Correspondence: [email protected] ABSTRACT Somatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet remain largely uncharacterized. To gain a better understanding of their distribution and functional impacts, we leveraged the genomic information contained in the transcriptome to uniformly call somatic mutations from over 7,500 tissue samples, representing 36 distinct tissues. This catalog, containing over 280,000 mutations, revealed a wide diversity of tissue- specific mutation profiles associated with gene expression levels and chromatin states. We found pervasive negative selection acting on missense and nonsense mutations, except for mutations previously observed in cancer samples, which were under positive selection and were highly enriched in many healthy tissues. These findings reveal fundamental patterns of tissue-specific somatic evolution and shed light on aging and the earliest stages of tumorigenesis. INTRODUCTION In humans, somatic mutations play a key role in senescence and tumorigenesis1. Pioneering work on somatic evolution in cancer has led to the characterization of cancer driver genes2 and mutation signatures3; the interplay between chromatin, nuclear architecture, carcinogens and the mutational landscape4–7; the evolutionary forces acting on somatic mutations8–11; and clinical implications of somatic mutations12.
    [Show full text]
  • Relationship Between Somatic Mutation and Neoplastic
    Reprinted from Proc. Nati. Acad. Sci. USA Vol. 75, No. 7, pp. 3297-3301, July 1978 Cell Biology Relationship between somatic mutation and neoplastic transformation (chemical carcinogenesis/Syrian hamster/anchorage independence/morphological transformation/neoplastic progression) J. CARL BARRETT* AND PAUL 0. P. Ts'o Division of Biophysics, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205 Communicated by James Bonner, April 10,1978 ABSTRACT Somatic mutation and neoplastic transforma- which are associated with transformed cells have been studied tion of diploid Syrian hamster embyro cells were examined extensively (5). Thus, somatic mutation and neoplastic trans- concomitantly. Mutations induced by benzo[a pyrene and N- methyl-N'-nitro-N-nitrosoguanidine were quantitated at the formation can be investigated by the same experimental ap- hypoxanthine phosphoribosyltransferase and Na+/K+ ATPase proach-i.e., by studying the heritable alterations of cells in loci and compared to phenotypic transformations measured by culture. The elucidation of the significance of these cellular changes in cellular morphology and colony- formation in agar. changes to tumorigenicity is crucial to an understanding of Both cellular transformations ad characteristics distinct from neoplastic transformation (5). To date, however, somatic the somatic mutations observed at the two loci. Mohological mutation and neoplastic transformation have not been transformation was observed after a time comparale to that studied of somatic mutation but at a frequency that was 25- to 540-fold quantitatively in the same cellular system, thus preventing higher. Transformants capable ofcolony formation in agar were direct comparisons of the two processes. detected at a frequency of 10-5-106, but not until 32-75 pop- Recently, we reported the development of a mammalian ulation doublings after carcinogen treatment.
    [Show full text]
  • Somatic and Germinal Mutations of Tumor-Suppressor Genes in the Development of Cancer
    Somatic and Germinal Mutations of Tumor-Suppressor Genes in the Development of Cancer MASAO S. SASAKI1, MITSUO KATO1, JUNYA TOGUCHIDA1, TOSHIKAZU YAMAGUCHI1, YOSUKE EJIMA1, KANJI ISHIZAKI1, AKIHIRO KANEKO2, AND HIROSHI TANOOKA21 RadiationBiology Center, Kyoto University,Sakyo-ku, Kyoto 606 2 NationalCancer Center , Chuo-ku,Tokyo 104, Japan. (ReceivedDecember 6, 1990) RB gene/mutation/parentalorigin/mutational mosaics/delayed mutation It is generallythought that the germinalmutation of tumor-suppressorgenes predisposesthe affected childrento the developmentof certaintypes of hereditarytumors while the somaticmutation of the same genes links to the developmentof non-hereditarytumors. Retinoblastomasusceptibility gene (RB gene) is a prototypeof such genes.We studied the parentalorigin of new mutationof the RB gene in the spor adic hereditaryand non-hereditaryretinoblastoma and osteosarcoma.The resultsshowed a preferential involvementof parentalgenome in the new germinalas wellas initialsomatic mutations. The male-directed mutagenesiseven in the somaticcells has been implicatedas a reflectionof germinalorigin of mutation,even for non-hereditarytumors as a manifestationof mutationalmosaicism associated with delayedmutation. The importanceof the newmutations occurring as mosaicsshould be emphasizedin the evaluationof cancerrisks from parentalexposures to radiationand chemicals. INTRODUCTION Evidence has been accumulated for the involvement of the loss-of-function mutation of the negative regulatory genes, i.e., tumor-suppressor genes, in the development of a variety of human cancers, particularly solid tumors',2). Retinoblastoma susceptibility gene (RB gene) is a prototype of such genes. Its loss-of-function mutation predisposes to the devel opment of retinoblastoma and osteosarcoma. The mutations are either germinal or somatic; the germinal mutation involving RB gene leading to the development of hereditary tumors while the somatic mutation of the same gene is manifested as non-hereditary tumors.
    [Show full text]
  • Somatic Mutations, Germ-Line Mutations, and Breast
    CANCER overview compare: stem cells SOMATIC MUTATIONS, • Class of diseases controlled cell division • Uncontrolled cell division GERM-LINE MUTATIONS, • Spread to adjacent tissues AND BREAST CANCER METASTASIS cancer cells spread by READING: pp. 202-220 bloodstream or lymphatic system BREAST CANCER Carcinoma:Carcinoma: EpithelialEpithelial cells.cells. Most commoncommon formsforms ofof breast,breast, prostate,prostate, lung,lung, coloncolon cancer.cancer. LymphomaLymphoma andand Leukemia:Leukemia: Blood,Blood, bonebone marrow cellscells Sarcoma:Sarcoma: ConnectiveConnective tissue,tissue, oror mesenchymal cellscells Mesothelioma: Mesothelial cellscells lininglining thethe peritoneum,peritoneum, pleura.pleura. Glioma:Glioma: GliaGlia (brain(brain cell)cell) NEW CASES OF CANCER U.S. 2002 Site Number of new cases Skin 800,000 When normal cells are damaged beyond repair, they are eliminated by apoptosis (programmed cell death). Breast (female) 203,500 Prostate 189,000 Lung 169,400 Cancer cells avoid apoptosis and continue to multiply in an uncontrolled manner Colon-rectum 148,300 Urinary system 90,000 Uterus 52,300 Pancreas 30,300 Ovary 23,300 1/31/3 individualsindividuals will olderolder adultsadults -- 1/41/4 ofof allall deathsdeaths duedue toto cancercancer getget somesome formform ofcancerofcancer 1 in 8 women BREAST CANCER SEPARATION OF SOMATIC CELL (some demographics) expected to be LINE AND GERM LINE diagnosed sometime during their lives Breast cancer occurs more often in white + 41,000 US women women than African will die this year
    [Show full text]
  • Adaptive Immunity
    34 Adaptive Immunity 1 Copyright © McGraw-Hill Global Education Holdings, LLC. Permission required for reproduction or display. 34.6 B-cell Biology 1. Describe the B-cell receptor structure and function 2. Illustrate the B-cell maturation process in response to antigen triggering 3. Compare T-dependent and T-independent B-cell activation 4. Build a model of the molecular events resulting in B-cell activation 2 B-Cell Biology • B cells must be activated by a specific antigen to continue mitosis – cells then replicate and differentiate into plasma cells which secrete antibodies • B cells have immunoglobulin receptors for the specific antigen that will activate that particular B cell – these receptors associate with other proteins and are called B-cell receptors (BCRs) • Interaction with that antigen is communicated to the nucleus via a signal transduction pathway similar to that described for T cells 3 4 B-Cell Activation • Leads to proliferation and differentiation into plasma cells – some cytokines produced by helper T cells can act on B cells and assist in growth and differentiation • Typically antigen-specific • Two mechanisms for antigen-specific activation – T dependent – T independent 5 T-Dependent Antigen Triggering • Like T cells, require two signals – antigen-BCR specific interaction – activated T helper 2 binds B cell presented antigen and secretes B cell growth factors • B cell differentiates into plasma cell and memory cell 6 T-Independent Antigen Triggering • T-independent antigens – polymeric antigens with large number of identical epitopes (e.g., bacterial lipopolysaccharides) • Less effective than T-dependent B cell activation – antibodies produced have a low affinity for antigen – no memory B cells formed 7 34.7 Antibodies 1.
    [Show full text]
  • Enhanced Somatic Mutation Rates Induced in Stem Cells of Mice by Low Chronic Exposure to Ethylnitrosourea (Dose Rate/Intestine/D1b-1/Laci) P
    Proc. Natl. Acad. Sci. USA Vol. 92, pp. 11470-11474, December 1995 Genetics Enhanced somatic mutation rates induced in stem cells of mice by low chronic exposure to ethylnitrosourea (dose rate/intestine/D1b-1/lacI) P. M. SHAVER-WALKER, C. URLANDO, K. S. TAO*, X. B. ZHANG, AND JOHN A. HEDDLEt Department of Biology, York University, Toronto, ON, Canada M3J 1P3 Communicated by Richard B. Setlow, Brookhaven National Laboratory, Upton, NY, August 21, 1995 (received for review April 28, 1995) ABSTRACT We have found that the somatic mutation these sites can be detected by means of peroxidase staining of rate at the Dlb-1 locus increases exponentially during low daily the small intestine after reaction with peroxidase-bound lectin. exposure to ethylnitrosourea over 4 months. This effect, In the small intestine, the Dlb-1b allele (presence of the binding enhanced mutagenesis, was not observed at a lacI transgene in site) is dominant over the Dlb-la allele (absence of the binding the same tissue, although the two loci respond very similarly site). In heterozygous mice (Dlb-lb/Dlb-la), mutation of the to acute doses. Since both mutations are neutral, the mutant dominant Dlb-1b allele in an intestinal stem cell results in a frequency was expected to increase linearly with time in mutant clone that lacks the lectin binding site and is unstained response to a constant mutagenic exposure, as it did for lacI. by the peroxidase. Since the stem cells of the small intestine are Enhanced mutagenesis does not result from an overall sen- located in the crypts (invaginations of the cell sheet) and feed sitization ofthe animals, since mice that had first been treated cells inward to the villi (projections of the cell sheet into the with a low daily dose for 90 days and then challenged with a lumen of the intestine), a mutant stem cell produces a ribbon large acute dose were not sensitized to the acute dose.
    [Show full text]
  • Immune Response (Somatic Mutation/Antibody Affinity/Combinational Diversity/Clonal Selection/Network Regulation) LAWRENCE WYSOCKI, TIM MANSER, and MALCOLM L
    Proc. Natl. Acad. Sci. USA Vol. 83, pp. 1847-1851, March 1986 Immunology Somatic evolution of variable region structures during an immune response (somatic mutation/antibody affinity/combinational diversity/clonal selection/network regulation) LAWRENCE WYSOCKI, TIM MANSER, AND MALCOLM L. GEFTER Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 Communicated by Herman N. Eisen, October 17, 1985 ABSTRACT Immunization of strain A mice with p- the hapten, p-azophenylarsonate (Ars). An average of50% of azophenylarsonate-conijugated protein stimulates B cells that the anti-Ars antibodies obtained from hyperimmunized strain synthesize anti-p-azophenylarsonate antibodies. A large frac- A mice are serologically related by cross-reaction with a V tion of these cells produce antibodies with variable (V) regions region-specific antiserum that defines the predominant strain encoded by a single heavy chain V gene segment together with A cross-reactive idiotype, denoted as CRI-A or IdCR (13-15). multiple combinations of diversity, heavy chain joining, light Limitations on the serologically defined idiotype as a phe- chain variable, and light chain joining gene segments. Early in notypic marker for clonally related antibodies, however, the immune response, these V regions are not somatically have prompted us to analyze V regions by determining their mutated. One of these V regions is initially expressed by only primary structures and the V gene segment combinations a minority of the responding B cells but binds p-azophenylar- encoding them. This methodology allows us to monitor the sonate with the highest affinity. After a secondary immuniza- selection of related of B cells and to tion, B cells synthesizing mutated derivatives of this single V clonally populations region dominate the response and bind p-azophenylarsonate correlate selection of these clones with the structures and with even higher afflinity than does the unmutated V region.
    [Show full text]