Skip to main content
SpringerLink
Log in

Instability at Chromosomal Fragile Sites

  • Conference paper
Genes and Environment in Cancer

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 154))

Abstract

Chromosomal fragile sites are loci that are especially prone to forming gaps or breaks on metaphase chromosomes when cells are cultured under conditions that inhibit DNA replication or repair. The relationship of “rare” folate sensitive fragile sites with (CCG)n expansion and, in some cases, genetic disease is well established. Although they comprise the vast majority of fragile sites, much less is known at the molecular level about the “common” fragile sites. These fragile sites may be seen on all chromosomes as a constant feature. In addition to forming fragile sites on metaphase chromosomes, they have been shown to display a number of characteristics of unstable and highly recombinogenic DNA in vitro, including chromosome rearrangements, sister chromatid exchanges and, more recently, intrachromosomal gene amplification. Only one such fragile site, FRA3B at 3p14.2, has been extensively investigated at the molecular level. It extends over a broad region of possibly 500 kb, and no trinucleotide or other simple repeat motifs have been identified in the region. FRA3B has recently been shown to lie within the FHIT gene locus. This region and the FHIT gene are unstable in a number of tumors and tumor cell lines. It thus appears that common fragile sites are also associated with unstable regions of DNA in vivo, at least in some tumor cells, and may cause this instability. Current challenges include determining the mechanism of fragile site expression and instability, and both the environmental and genetic factors that influence this process. Candidate factors include those genes involved in DNA repair and cell cycle and common carcinogens such as those in cigarette smoke.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
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.

References

  • Austin MJF, Collins IM, Corey LA, Nance WE, Neale MC et al (1992) Aphidicolin-inducible common fragile-site expression: results from a population survey of twins. Am J Hum Genet. 50: 76–83

    PubMed  CAS  Google Scholar 

  • Ban S, Cologne JB, Neriishi K (1995) Effect of radiation and cigarette smoking on expression of FUdR-inducible common fragile sites in human peripheral lymphocytes. Mutat Res 334: 197–203

    PubMed  CAS  Google Scholar 

  • Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M, Huebner K. (1996) FHIT, a putative tumor suppressor in humans, is a di-nucleoside 5’,5“’-P1,P3-triphosphate hydrolase. Biochemistry 35:11529–11535

    Google Scholar 

  • Boldog F, Gemmill R, West J, Robinson M, Li E (1997) Chromosome 3p14 homozygous deletions and sequence analysis of FRA3B. Hum Mol Genet 6: 193–203

    Article  PubMed  CAS  Google Scholar 

  • Cleton-Jansen AM, Moerland EW, Kuipers-Dijkshoorn NJ, Callen DF, Sutherland GR et al (1994) At least two different regions are involved in allelic imbalance on chromosome arm 16q in breast cancer. Genes Chromosomes Cancer 9: 101–107

    Article  PubMed  CAS  Google Scholar 

  • Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S et al (1979) Hereditary renal-cell carcinoma associated with a chromosomal translocation. New Engl J Med 301: 592–595

    Article  PubMed  CAS  Google Scholar 

  • Coquelle A, Pipiras E, Toledo F, Buttin G, Debatisse M (1997) Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplications. Cell 89: 215–225

    Article  PubMed  CAS  Google Scholar 

  • De Braekeleer M, Sreekantaiah C, Haas 0 (1992) Herpes simplex virus and human papillomavirus sites correlate with chromosomal breakpoints in human cervical carcinoma. Cancer Genet Cytogenet 59: 135–137

    Article  PubMed  Google Scholar 

  • Donehower LA, Godley LA, Aldaz CM, Pyle R, Shi YP, Pinkel D, Gray J, Bradley A, Medina D, Varmus HE (1995) Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability. Genes & Development 9: 882–895

    Article  CAS  Google Scholar 

  • Fu YH, Kuhl DPA, Pizzut A, Pierett M, Sutcliffe JS et al (1991) Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67: 1047–1058

    Article  PubMed  CAS  Google Scholar 

  • Gacy AM, Goellner G, Juranic N, Macura S, McMurray CT (1995) Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell 81: 533–540

    Article  PubMed  CAS  Google Scholar 

  • Garrison PN, Mathis SA, Barnes LD (1986) In vivo levels of diadenosine tetraphosphate and adenosine tetraphospho-guanosine in Physarum polycephalum during the cell cycle and oxidative stress. Mol Cell Biol 6: 1179–1186

    PubMed  CAS  Google Scholar 

  • Geurts JMW, Schoenmakers EFPM, Roijer E, Stenman G, Van de Ven WJM (1997) Expression of reciprocal hybrid transcripts of HMGIC and FHIT in a pleomorphic adenoma of the parotid gland. Cancer Res 57: 13–17

    Google Scholar 

  • Glover TW (1998) Common fragile sites. In: Wells RD, Warren ST (eds) Genetic instabilities and neurological diseases. Academic Press, San Diego, pp 75–83

    Google Scholar 

  • Glover TW, Stein CK (1987) Induction of sister chromatid exchanges at common fragile sites. Am J Hum Genet 41: 882–890

    PubMed  CAS  Google Scholar 

  • Glover TW, Stein CK (1988) Chromosome breakage and recombination at fragile sites. Am J Hum Genet 43: 265–273

    PubMed  CAS  Google Scholar 

  • Glover TW, Berger C, Coyle J, Echo B (1984) DNA polymerase a inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum Genet 67: 136–142

    Article  PubMed  CAS  Google Scholar 

  • Glover TW, Coyle-Morris J, Morgan R (1986) Fragile sites: overview, occurrence in acute nonlymphocytic leukemia-M4 and effects of caffeine on expression. Cancer Genet Cytogenet 19: 141–150

    Article  PubMed  CAS  Google Scholar 

  • Glover TW, Coyle-Morris JF, Li, FP, Brown RS, Berger CS (1988) Translocation t (3;8) (p14.2;q24.1) in renal cell carcinoma affects expression of the common fragile site at 3p14 (FRA3B) in lymphocytes. Cancer Genet Cytogenet 31: 69–73

    Article  PubMed  CAS  Google Scholar 

  • Hecht F, Sutherland GR (1984) Fragile sites and cancer breakpoints. Cancer Genet Cytogenet 12: 179–181

    Article  PubMed  CAS  Google Scholar 

  • Hecht F (1988) Fragile sites, cancer chromosome breakpoints, and oncogenes all cluster in light G-bands. Cancer Genet Cytogenet 31: 17–24

    Article  PubMed  CAS  Google Scholar 

  • Hecht F, Glover TW (1984) Cancer chromosome breakpoints and common fragile sites induced by aphidicolin. Cancer Genet Cytogenet 13: 185–188

    Article  PubMed  CAS  Google Scholar 

  • Hibi K, Takahashi T, Yamakawa K, Ueda R, Sekido Y et al (1992) Three distinct regions involved in 3p deletion in human lung cancer. Oncogene 7: 445–449

    PubMed  CAS  Google Scholar 

  • Huang H, Qian C, Jenkins R, Smith D (1998) FISH mapping of YAC clones at human chromsomal band 7q31.2: Identification of YACs spanning FRA7G within the common region of LOH in breast and prostate cancer. Genes Chromosomes Cancer 21: 152–159

    Article  PubMed  CAS  Google Scholar 

  • Huang LC, Clarkin KC, Wahl GM (1996) Sensitivity and selectivity of the DNA damage sensor responsible for activating p53-dependent G1 arrest. Proc Natl Acad Sci 93: 4827–4832

    Article  PubMed  CAS  Google Scholar 

  • Jalal SM, Lindor NM, Michels VV, Buckley DD, Hoppe DA, Sarkar G, Dewald GW (1993) Absence of chromosome fragility at 19q13.3 in patients with myotonic dystrophy. Am J Med Genet 46: 441–439

    Article  PubMed  CAS  Google Scholar 

  • Jeffreys AJ, Tamaki K, MacLeod A, Monckton DG, Neil DL et al (1994) Complex gene conversion events in germline mutation at human satellites. Nat Genet 6: 136–145

    Article  PubMed  CAS  Google Scholar 

  • Jones C, Penny L, Mattina T, Yu S, Baker E, Voullaire L, Langdon WY, Sutherland GR, Richards RI, Tunnacliffe A (1995) Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2. Nature 376: 145–149

    Article  PubMed  CAS  Google Scholar 

  • Kang S, Ohshima K, Shimizu M et al (1995) Pausing of DNA synthesis in vitro at specific loci in CGT and CGG triplet repeats from human hereditary disease genes. J Biol Chem 270: 27014–27021

    Article  PubMed  CAS  Google Scholar 

  • Kastury K, Baffa R, Druck, T, Ohta M, Cotticelli MG, Inoue H, Negrini M, Rugge M., Huang D, Croce CM, Palazzo J, Huebner K (1996) Potential gastrointestinal tumor suppressor locus at the 3p14.2 FRA3Bsite identified by homozygous deletions in tumor cell lines. Cancer Res 56: 978–983

    PubMed  CAS  Google Scholar 

  • Knight SJL, Flannery AV, Hirst AC, Campbell L, Christodoulou Z et al (1993) Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell 74: 1–20

    Article  Google Scholar 

  • Kuo MT, Vyas RC, Jiang LX, Hittelman WN (1994) Chromosome breakage at a major fragile site associated with P-glycoprotein gene amplification in multidrug-resistant CHO cells. Mol Cell Biol 14: 5202–5211

    PubMed  CAS  Google Scholar 

  • Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K et al (1991) Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252: 1711–1718

    Article  PubMed  CAS  Google Scholar 

  • Laird C, Jaffe E, Karpsen G, Lamb M, Nelson R (1987) Fragile sites in human chromosomes as regions of late-replicating DNA. Trends Genet 3: 274–281

    Article  CAS  Google Scholar 

  • Le Beau MM, Rowley JD (1984) Heritable fragile sites and cancer. Nature 308: 607–608

    Article  Google Scholar 

  • Le Beau MM, Rassool FV, Neilly ME, Espinosa R, Glover TW, Smith DI, McKeithan TW (1998) Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction. Hum Mol Genet 7: 755–761

    Article  PubMed  Google Scholar 

  • Lisitsyn NA, Lisitsina NM, Dalbagni G, Barker P, Sanchez CA, Gnarra J, Linehan WM, Reid BJ, Wigler MH (1995) Proc Natl Acad Sci USA 92: 151–155

    Article  PubMed  CAS  Google Scholar 

  • Michael D, Beer DG, Wilke CM, Miller DM, Glover TW (1997) Frequent deletions of FHIT and FRA3B in Barrett’s metaplasia and esophageal adenocarcinomas. Oncogene 15: 1653–1659

    Article  PubMed  CAS  Google Scholar 

  • Muller CY, O’Boyle JD, Fong KM, Wistuba II, Biesterveld E, Ahmadian M, Miller DS, Gazdar AF, Minna JD (1998) Abnormalities of FHIT genomic and cDNAs in human cervical cancer with HPV subtype correlation. J Natl Cancer Inst (in press)

    Google Scholar 

  • Nancarrow JK, Kremer E, Holman K, Eyre H, Dogget NA, Le Paslier D, Callen DF, Sutherland GR, Richards RI (1994) Implications of FRA16A structure for the mechanism of chromosomal fragile site genesis. Science 264: 1938–1941

    Article  PubMed  CAS  Google Scholar 

  • Negrini M, Monaco C, Vorechovsky I, Ohta M, Druck T, Baffa R., Huebner K, Croce CM (1996) The FHIT gene at 3p14.2 is abnormal in breast carcinomas. Cancer Res 56: 3173–3179

    PubMed  CAS  Google Scholar 

  • Oberle I, Rousseau F, Heitz D, Kretz C, Deveys D et al (1991) Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252: 1097–1102

    Article  CAS  Google Scholar 

  • Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K (1996) The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84: 587–597

    Article  PubMed  CAS  Google Scholar 

  • Pardee W, Mullins C, He Z, Glover TW, Wilke C, Opalka B, Schutte J, Smith DI (1995) Precise localization of aphidicolin-induced breakpoints on the short arm of human chromosome 3. Genomics 27: 358–361

    Article  Google Scholar 

  • Pardee W, Wilke CM, Hoge A, Glover TW, Smith DI (1996) A 350 Kb cosmid contig in 3p14.2 that crosses the t(3;8) hereditary renal cell carcinoma translocation breakpoint and 17 aphidicolin-induced FRA3B breakpoints. Genomics 35: 87–93

    Article  Google Scholar 

  • Parrish P, Oostra BA, Verkerk AJMH, Richards, CS et al (1994) Isolation of a GCC repeat showing expansion in FRAXF, a fragile site distal to FRAXA and FRAXE. Nature [Genet] 8: 229–235

    Article  CAS  Google Scholar 

  • Popescu NC, DiPaolo JA (1989) Preferential sites for viral integration on mammalian genome. Cancer Genet Cytogenet 42: 157–171

    Article  PubMed  CAS  Google Scholar 

  • Rassool FV, McKeithan TW, Neilly ME, van Melle E, Espinosa R III, Lebeau MM (1991) Preferential integration of marker DNA into the chromosomal fragile site at 3p14: An approach to cloning fragile sites. Proc Natl Acad Sci USA 88: 6657–6661

    Article  PubMed  CAS  Google Scholar 

  • Rassool FV, Le Beau MM, Shen ML, Neilly ME, Espinosa R III, Ong ST, Boldog F, Drabkin H, McCarroll R, McKeithan TW (1996) Direct cloning of DNA sequences from the common fragile site region at chromosome band 3p14.2. Genomics 35: 109–117

    Article  PubMed  CAS  Google Scholar 

  • Richards RI, Sutherland GR (1994) Simple repeat DNA is not replicated simply. Nat Genet 6: 114–116

    Article  PubMed  CAS  Google Scholar 

  • Segal E, Le Pecq JB (1986) Relationship between cellular diadenosine 5’, 5“’-P1, P4-tetraphosphate level, cell density, cell growth stimulation and toxic stresses. Exp Cell Res 167: 119–126

    Google Scholar 

  • Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK Eryomin V, Sard L, Tagliabue E, Greco A, Fusetti L, Schwartz G, Pierotti MC, Croce CM, Huebner K (1997) Replacement of Fhit in cancer cells supresses tumorigenicity. Proc Natl Acad Sci USA 94: 13771–13776

    Article  PubMed  CAS  Google Scholar 

  • Smith PP, Friedman C, Bryant EM, McDougall JK (1992) Viral integration and fragile sites in human papillomavirus-immortalized human keratinocyte cell lines. Genes Chromosomes Cancer 5: 150–157

    Article  PubMed  CAS  Google Scholar 

  • Sozzi G, Veronese ML, Negrini M, Baffa R, Cotticelli MG, Inoue H, Tornielli S, Pilotti S, De Gregorio L, Pastorino U, Pierotti MA, Ohta M, Huebner K, Croce CM (1996) The FHIT gene 3p14.2 is abnormal in lung cancer. Cell 85: 7–26

    Article  Google Scholar 

  • Sozzi G, Sard L, De Gregorio L, Marchetti A, Musso K et al (1997) Association between cigarette smoking and FHIT gene alterations in lung cancer. Cancer Res. 57:2121–2123

    Google Scholar 

  • Sutherland GR, Hecht F (1985) Fragile sites on human chromosomes Oxford University Press, Oxford (Oxford Monographs on Medical Genetics)

    Google Scholar 

  • Tedeschi B, Vernole P, Sanna ML, Nicoletti B (1992) Population cytogenetics of aphidicolininduced fragile sites. Hum Genet 89: 543–547

    Article  PubMed  CAS  Google Scholar 

  • Thiagalingam S, Lisitsyn, NA, Hamaguchi M, Wigler MH, Willson JK, Markowitz SD, Leach FS, Kinzler KW, Vogelstein B (1996) Evaluation of the FHIT gene in colorectal cancers. Cancer Res 56: 2936–2939

    PubMed  CAS  Google Scholar 

  • Verkerk AJM, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP et al (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65: 905–914

    Article  PubMed  CAS  Google Scholar 

  • Virgilio L, Shuster M, Gollin SM, Veronese ML, Ohta M, Huebner K, Croce CM (1996) FHIT gene alterations in head and neck squamous cell carcinomas. Proc Natl Acad Sci USA 93:9770–9775

    Google Scholar 

  • Wang ND, Testa JR, Smith DI (1993) Determination of the specificity of aphidicolin-induced breakage of the human 3p14.2 fragile site. Genomics 17: 341–347

    Article  PubMed  CAS  Google Scholar 

  • Wang YH, Griffith J (1996) Methylation of expanded CCG triplet repeat DNA from fragile X syndrome patients enhances nucleosome exclusion. J Biol Chem 271: 22937–22940

    Article  PubMed  CAS  Google Scholar 

  • Warren ST (1996) The expanding world of trinucleotide repeats. Science 271: 1374–1375

    Article  PubMed  CAS  Google Scholar 

  • Wilke CM, Hall BK, Buldog F, Gemmill RM, Chandrasekharappa C, Drabkin H, Glover TW (1994) Multicolor FISH mapping of YAC clonec in 3p14 and isolation of a YAC spanning both FRA3B and the t(3;8) translocation associated with heritable renal cell Carcinoma. Genomics 22: 319–326

    Article  PubMed  CAS  Google Scholar 

  • Wilke CM, Hall BK, Hoge A, Pardee W, Smith DI, Glover TW (1996) FRA3B extends over a broad region and contains a spontaneous HPV integration site: Direct evidence for the coincidence of viral integration sites and fragiles sites. Hum Mol Genet 5: 187–195

    Google Scholar 

  • Wistuba II, Montellano FD, Milchgrub S, Virmani AK, Behrens C, Chen H, Ahmadian M, Nowak JA, Muller C, Minna JD, Gazdar AF (1997) Deletions of chromosome 3p are frequent and early events in the pathogenesis of uterine cervical carcinoma. Cancer Res 57: 3154–3158

    PubMed  CAS  Google Scholar 

  • Yunis JJ, Soreng AL (1984) Constitutive fragile sites and cancer. Science 226: 1199–1204

    Article  PubMed  CAS  Google Scholar 

  • Yu S, Mangelsforf M, Hewett D, Hobsen L et al (1997) Human chromosomal fragile site FRA16B is an amplified AT-rich minisatellitte repeat. Cell 88: 367–374

    Article  PubMed  CAS  Google Scholar 

  • Yamakawa K, Morita R, Takahashi E, Hori T, Ishikawa J et al (1991) A detailed deletion mapping of the short arm of chromosome 3 in sporadic renal cell carcinoma. Cancer Res 51: 4707–4711

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Deparmtents of Pediatrics and Human Genetics, 4708 Medical Sciences II, University of Michigan, Ann Arbor, MI, 48109-0618, USA

    T. W. Glover

Authors
  1. T. W. Glover
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Abteilung Zytogenetik, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany

    Manfred Schwab

  2. Pathologisches Institut, Universität München, Thalkirchner Straße 36, D-80377, München, Germany

    Hartmut M. Rabes

  3. Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany

    Klaus Munk

  4. Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, D-82152, Martinsried, Germany

    Hans Peter Hofschneider

Rights and permissions

Reprints and permissions

Copyright information

© 1998 Springer-Verlag Berlin · Heidelberg

About this paper

Cite this paper

Glover, T.W. (1998). Instability at Chromosomal Fragile Sites. In: Schwab, M., Rabes, H.M., Munk, K., Hofschneider, H.P. (eds) Genes and Environment in Cancer. Recent Results in Cancer Research, vol 154. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-46870-4_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-46870-4_11

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-46872-8

  • Online ISBN: 978-3-642-46870-4

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation