Trends in Genetics
Volume 17, Issue 6, 1 June 2001, Pages 339-345
Journal home page for Trends in Genetics

Review
Fragile and unstable chromosomes in cancer: causes and consequences

https://doi.org/10.1016/S0168-9525(01)02303-4Get rights and content

Abstract

Cancer cells commonly exhibit various forms of genetic instability, such as changes in chromosome copy number, translocations and point mutations in particular genes. Although transmissible change seems to be an essential part of the neoplastic process, the extent to which DNA instability is a cause rather than a consequence of cancer is unclear. Chromosomal fragile sites have been proposed to be not only susceptible to DNA instability in cancer cells, but also associated with genes that contribute to the neoplastic process. Mutation at fragile site loci might therefore have a causative role in cancer. Recent studies on one class of human chromosomal fragile sites show that instability at fragile site loci can functionally contribute to tumor cell biology.

Section snippets

Where do fragile sites fit in the spectrum of chromosomal instability in cancer?

The most frequently observed chromosomal instability in cancer cells is aneuploidy – change from the normal number of chromosomes, which usually involves several chromosomes. Aneuploidy has been proposed as necessary for (at least certain forms of) cancer 20. Certainly, cell transformation by some cancer-associated single genes, such as those encoding T antigen or cyclin D, can lead to dramatic changes in chromosome copy number 20, 21. The simplest outcome of such chromosomal changes would be

Role of FHIT/FRA3B in cancer

A wide variety of tumor types have FRA3B deletions. Many of these are adenocarcinomas of the tissues exposed to the environment, for example gastrointestinal tract and lung. On this basis it has been proposed that common fragile site loci are particularly sensitive to environmental mutagens 35. The FHIT gene was found to span the FRA3B fragile site 15. Since its discovery over 200 articles concerning the FHIT gene and/or protein have been published, including controversy over whether FHIT has a

Conclusions

A substantial body of evidence now supports the proposal that at least some common chromosomal fragile sites predispose to DNA instability in cancer cells. Although the nature and extent of the contribution of this instability to cancer cell biology remains unclear, functional studies have provided some evidence supporting a role in neoplasia for the genes spanning (or near) at least two of these sites (FRA3B and FRA16D). It might be inappropriate to assume that what we know about some fragile

Acknowledgements

R.A.R. is an affiliate of the Dept of Molecular Biosciences, University of Adelaide. I thank Elizabeth Baker, Amanda Lumsden, Eric Haan, Merran Finnis, Sonia Dayan, Grant Sutherland and Nanshan Chang for comments on drafts of this review, Elizabeth Baker for Fig. 2 and for sharing her knowledge of chromosomal fragile sites, Eric Haan for particularly helpful suggestions, and Michelle DeBatisse and Cell Press for permission to reproduce Fig. 3. This work has been supported by grants from the

References (49)

  • A. Nishimura

    The timing of cell division: Ap4A as a signal

    Trends Biochem. Sci.

    (1998)
  • L. Sard

    The tumour-suppressor gene FHIT is involved in the regulation of apoptosis and in cell cycle control

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • T.W. Glover

    The murine Fhit gene is highly similar to its human orthologue and maps to a common fragile site region

    Cancer Res.

    (1998)
  • G.R. Sutherland

    Fragile sites

  • G.R. Sutherland

    Fragile sites still breaking

    Trends Genet.

    (1998)
  • S. Yu

    Human chromosomal fragile site FRA16B is an amplified minisatellite repeat

    Cell

    (1997)
  • F. Boldog

    Chromosome 3p14 homozygous deletions and sequence analysis of FRA3B

    Hum. Mol. Genet.

    (1997)
  • H. Inoue

    Sequence of the FRA3B common fragile site: Implications for the mechanism of FHIT deletion

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • K. Mimori

    Cancer-specific chromosome alterations in the constitutive fragile region FRA3B

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • H. Huang

    Fish mapping of YAC clones at human chromosomal band 7q31.2: identification of YACs spanning FRA7G within the common region of LOH in breast and prostate cancer

    Genes Chromosomes Cancer

    (1998)
  • H. Huang

    FRA7G extends over a broad region: coincidence of human endogenous retroviral sequences (HERV-H) and small polydispersed circular DNAs (spcDNA) and fragile sites

    Oncogene

    (1998)
  • D. Mishmar

    Molecular characterisation of a common fragile site (FRA7H) on human chromosome 7 by the cloning of an SV40 integration site

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • A.P. Craig-Holmes

    Variation in the expression of aphidicolin-induced fragile sites in human lymphocyte cultures

    Hum. Genet.

    (1987)
  • M. Ohta

    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

    (1996)
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