Trends in Genetics
ReviewFragile and unstable chromosomes in cancer: causes and consequences
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
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