Skip to main content
SpringerLink
Log in

Genomic Instability and Its Role in Neoplasia

  • Chapter
Genetic Instability and Tumorigenesis

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 221))

Abstract

The study of how genomic integrity is regulated is important not only in the formation and progression of a neoplasia, but also in how a tumor responds to therapy. Genomic instability has been hypothesized to be a driving force behind multistep carcinogenesis (Nowell 1976). A number of genetic changes are required for a normal cell to become tumorigenic (Foulds 1959; Fearon and Vogelstein 1990). If genomic instability increases the rate at which these alterations occur, then the accumulation of changes and subsequent selection for growth and motility advantage may lead to the formation of a neoplasia. Thus, the new variants generated during tumor progression may be fueled by an underlying genomic instability. Once a cell becomes neoplastic, its evolution may continue to malignancy. Further genetic changes are required to confer metastatic properties on the tumor cell. These properties include the ability to invade surrounding tissues, enter the vasculature, extravasate, and colonize a secondary site. Proficiency at each step is necessary for a tumor cell to become fully metastatic. Genetic alterations are the basis for this acquired variation (Rubin 1987; Liotta et al. 1987). The emergence of drug-resistant or radiation-resistant variants is one of the most disappointing aspects of treating a neoplasia. These variants are generated by the same forces that allow the tumor to become established and progress.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  • Band V, Zajchowski D, Stenman G, Morton CC, Kulesa V, Connolly J, Sager R (1989) A newly established metastatic breast tumor cell line with integrated amplified copies of ERBB2 and double minute chromosomes. Genes Chrom Cancer 1: 48–58

    Article  PubMed  CAS  Google Scholar 

  • Biedler JL, Spengler BA (1976) Metaphase chromosome anomaly: association with drug resistance and cell-specific products. Science 191: 185–187

    Article  PubMed  CAS  Google Scholar 

  • Brunborg G, Williamson DH (1978) The relevance of the nuclear division cycle in radiosensitivity in yeast. Mol Gen Genet 162: 277–286

    Article  PubMed  CAS  Google Scholar 

  • Chanet R, Williamson DH, Moustacchi E (1973) Cyclic variations in killing and ‘petite’ mutagenesis induced by ultraviolet light in synchronized yeast strains. Biochem Biophys Acta 324: 290–299

    PubMed  CAS  Google Scholar 

  • Cox D, Yuncken C, Spriggs AI (1965) Minute chromatin bodies in malignant tumors of childhood. Lancet 1: 55–58

    Article  PubMed  CAS  Google Scholar 

  • Dolnick BJ, Berenson RJ, Bertino JR, Kaufman RJ, Nunberg JH, Schimke RT (1979) Correlation of dihydrofolate reductase elevation with gene amplification in a homogeneously staining chromosomal region in L5178Y cells. J Cell Biol 83: 394–402

    Article  PubMed  CAS  Google Scholar 

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA, Butel JS, Bradley A (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356: 215–221

    Article  PubMed  CAS  Google Scholar 

  • Elmore E, Kakunaga T, Barrett JC (1983) Comparison of spontaneous mutation rates of normal and chemically transformed human skin fibroblasts. Cancer Res 43: 1650–1655

    PubMed  CAS  Google Scholar 

  • Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61: 759–767

    Article  PubMed  CAS  Google Scholar 

  • Foulds L (1959) Neoplastic development, vol 2. Academic, New York

    Google Scholar 

  • Gyuris J, Golemis E, Chertkov H, Brent R (1993) Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2. Cell 75: 791–803

    Article  PubMed  CAS  Google Scholar 

  • Hamlin JL, Leu T-H, Vaughn JP, Ma C, Dikwel PA (1991) Amplification of DNA sequences in mammalian cells. Prog Nucleic Acid Res 41: 203–239

    Article  CAS  Google Scholar 

  • Harper JW, Adami GR, Wei N, Keyornarsi K, Elledge SJ (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75: 805–816

    Article  PubMed  CAS  Google Scholar 

  • Hartwell L (1992) Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71: 543–546

    Article  PubMed  CAS  Google Scholar 

  • Hartwell L, Kastan M (1994) Cell cycle control and cancer. Science 266: 1821–1828

    Article  PubMed  CAS  Google Scholar 

  • Hartwell L, Weinert T (1989) Checkpoints: controls that ensure the order of cell cycle events. Science 246: 629–634

    Article  PubMed  CAS  Google Scholar 

  • Henry JA, Hennessy C, Levett DL, Lennard TW, Westley BR, May FE (1993) Int-2 amplification in breast cancer: association with decreased survival and relationship to amplification of c-erbB-2 and c-myc. Int J Cancer 53: 774–780

    Article  PubMed  CAS  Google Scholar 

  • Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51: 6304–6311

    PubMed  CAS  Google Scholar 

  • Kirsh IR, Abdallah JM, Bertness VL, Hale M, Lipkowitz S, Lista F, Lombardi DP (1994) Lymphocyte-specific genetic instability and cancer. Cold Spring Harb Symp Quant Biol 59: 287–295

    Google Scholar 

  • Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB (1992) Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 89: 7491–7495

    Article  PubMed  CAS  Google Scholar 

  • Lau CC, Pardee AB (1982) Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc Natl Acad Sci USA 79: 2942–2946

    Article  PubMed  CAS  Google Scholar 

  • Li F, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RA (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48: 5358–5362

    PubMed  CAS  Google Scholar 

  • Liotta LA, Guirguis R, Stracke M (1987) Review article: biology of melanoma invasion and metastasis. Pigment Cell Res 1: 5–15

    Article  PubMed  CAS  Google Scholar 

  • Livingstone LR, White AE, Sprouse J, Livanos E, Jacks T, Tlsty TD (1992) Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70: 923–935

    Article  PubMed  CAS  Google Scholar 

  • Lukas J, Pagano M, Staskova Z, Draetta G, Bartek J (1994) Cyclin D1 protein oscillates and is essential for cell cycle progression in human tumor cell lines. Oncogene 9: 707–718

    PubMed  CAS  Google Scholar 

  • Ma C, Martin S, Trask B, Hamlin JL (1993) Sister chromatid fusion initiates amplification of the dihydrofolate reductase gene in Chinese hamster cells. Genes Dev 7: 605–620

    Article  PubMed  CAS  Google Scholar 

  • McGill JR, Beitzel BF, Nielson JL, Walsh JT, Drabek SM, Meador RJ, Von Hoff DD (1993) Double minutes are frequently found in ovarian carcinomas. Canc Genet Cytogenet 71: 125–131

    Article  CAS  Google Scholar 

  • Moreno S, Nurse P (1994) Regulation of progression through the G1 phase of the cell cycle by the rum1 + gene. J Clin Oncol 367: 236–242

    CAS  Google Scholar 

  • Motokura T, Bloom T, Kim HG, Juppner H, Ruderman JV, Kronenberg HM, Arnold A (1991) A novel cyclin encoded by abcl1-linked candidate oncogene. Nature 350: 512–515

    Article  PubMed  CAS  Google Scholar 

  • Nelson WG, Kastan MB (1994) RDNA Strand Breaks: the DNA template alteration that trigger p53-dependent DNA damage response pathways. Mol Cell Biol 14: 1815–1823

    PubMed  CAS  Google Scholar 

  • Nishimoto TM, Eilen E, Basilico C (1978) Premature chromosome condensation in a ts DNA-mutant of BHK cells. Cell 15: 475–483

    Article  PubMed  CAS  Google Scholar 

  • Nowell P (1976) The clonal evolution of tumor cell populations. Science 194: 23–28

    Article  PubMed  CAS  Google Scholar 

  • Nunberg JH, Kaufman RJ, Schimke RT, Urlaub G, Chasin LA (1978) Amplified dihydrofolate reductase genes are localized to a homogeneous staining region of a single chromosome in a methotrexate-resistant Chinese hamster ovary cell line. Proc Natl Acad Sci USA 75: 5553–5556

    Article  PubMed  CAS  Google Scholar 

  • Pardee A (1974) A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA 71: 1286–1290

    Article  PubMed  CAS  Google Scholar 

  • Pines J (1993) Trends Biochem Sci 18: 195–197

    Article  PubMed  CAS  Google Scholar 

  • Rubin H (1987) The source of heritable variation in cellular growth capacities. Cancer Metastasis Rev 6: 85–89

    Article  PubMed  CAS  Google Scholar 

  • Schaefer DI, Livanos EM, White AE, Tlsty TD (1993) Multiple mechanisms of N-(phosphonoacetyl)-L-aspartate drug resistance in SV40-infected precrisis human fibroblasts. Cancer Res 53: 4946–4951

    PubMed  CAS  Google Scholar 

  • Schimke RT (1984) Gene amplification, drug resistance, and cancer. Cancer Res 44: 1735–1742

    PubMed  CAS  Google Scholar 

  • Schimke RT, Kaufman RJ, Alt FW, Kellems RF (1978) Gene amplification and drug resistance in cultured murine cells. Science 202: 1050–1055

    Article  Google Scholar 

  • Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KU, Hammond D (1985) Association of multiple copies of the n-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 313: 1111–1116

    Article  PubMed  CAS  Google Scholar 

  • Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366: 704–707

    Article  PubMed  CAS  Google Scholar 

  • Seshadri R, Kutlaca RJ, Trainor K et al (1987) Mutation rate of normal and malignant human lymphocytes. Cancer Res 47: 407–409

    PubMed  CAS  Google Scholar 

  • Sherr CJ (1993) Mammalian G1 cyclins. Cell 73: 1950–1965

    Article  Google Scholar 

  • Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182

    Article  PubMed  Google Scholar 

  • Stark GR, Wahl GM (1984) Gene amplification. Annu Rev Biochem 53: 447–491

    Article  PubMed  CAS  Google Scholar 

  • Swyryd EA, Seaver SS, Stark GR (1974) N-(phosphonacetyl)-L-aspartate, a potent transition state analog inhibitor of aspartate transcarbamylase, blocks proliferation of mammalian cells in culture. J Biol Chem 249: 6945–6969

    PubMed  CAS  Google Scholar 

  • Tam SW, Theodoras AM, Shay JW, Draeta GF, Pagano M (1994) Differential expression and regulation of cyclin D1 protein in normal and tumor human cells: association with Cdk4 is required for cyclin D1 function in G1 progression. Oncogene 9: 2663–2674

    PubMed  CAS  Google Scholar 

  • Tlsty TD, Jonczyk P, White A et al (1993) Loss of chromosomal integrity in neoplasia. Cold Spring Harbor Symp Quant Biol 58: 645–654

    PubMed  CAS  Google Scholar 

  • Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV (1994) Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369: 669–671

    Article  PubMed  CAS  Google Scholar 

  • Wahl GM, Padgett RA, Stark GR (1979) Gene amplification causes overproduction of the first three enzymes of UMP synthesis in N-(phosphonoacetyl)-L-aspartate-resistant hamster cells. J Biol Chem 254: 8679–8689

    PubMed  CAS  Google Scholar 

  • Weinert TA, Hartwell LH (1988) The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. Science 241: 317–322

    Article  PubMed  CAS  Google Scholar 

  • Weinert TA, Hartwell LH (1990) Characterization of RAD9 of Saccharomyces cerevisiae and evidence that its function acts posttranslationally in cell cycle arrest after DNA damage. Mol Cell Biol 10: 6554–6564

    PubMed  CAS  Google Scholar 

  • White AE, Livanos EM, Tlsty TD (1994) Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins. Genes Dev 8: 666–677

    Article  PubMed  CAS  Google Scholar 

  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366: 701–704

    Article  PubMed  CAS  Google Scholar 

  • Yin Y, Tainsky MA, Bischoff FZ, Strong LC, Wahl GM (1992) Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cel 70: 937–948

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of California at San Francisco, PO Box 0506, San Francisco, CA, 94143-0506, USA

    T. D. Tlsty

Authors
  1. T. D. Tlsty
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Johns Hopkins Hospital, Ross 345, 720 Rutland Avenue, Baltimore, MD, 21205, USA

    Michael B. Kastan M.D., Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1997 Springer Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Tlsty, T.D. (1997). Genomic Instability and Its Role in Neoplasia. In: Kastan, M.B. (eds) Genetic Instability and Tumorigenesis. Current Topics in Microbiology and Immunology, vol 221. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60505-5_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-60505-5_4

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64434-4

  • Online ISBN: 978-3-642-60505-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation