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Genomic instability — the engine of tumorigenesis?

Abstract

Human cancers harbour numerous mutations and it has been proposed that these result from some form of inherent genomic instability. Some cancers have proven genomic instability or features that are indicative of this. Inherited cancer syndromes exist that are caused by deficient DNA repair or chromosomal integrity. By contrast, theoretical analysis and experimental data from sporadic colorectal tumours provide little general evidence of genomic instability in early lesions. These apparently conflicting data raise the question of whether or not genomic instability is necessary for driving tumour growth, and whether or not it is the usual initiating event in tumorigenesis.

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Figure 1: Schematic model of selection and mutation in the somatic evolution of tumours.
Figure 2: A simplified model of the associations between the 'first hit' and 'second hit' at APC in colorectal tumours — selection for optimal levels of WNT signalling.

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Acknowledgements

We are grateful to W. Bodmer for consistently thought-provoking discussion, and to many others in the field (J. Cairns, P. Nowell, L. Loeb, B. Vogelstein and others) with whom we might or might not always agree, but whose views continue to provide challenges and food for thought. The authors are supported by Cancer Research UK and grants from the Boehringer Ingelheim Fonds (to O.M.S.) and the Swiss National Science Foundation (to K.H.).

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Correspondence to Ian P. M. Tomlinson.

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DATABASES

Cancer.gov

Colorectal cancer

endometrial cancer

LocusLink

APC

BUB1

KRAS

MLH1

MSH2

MYH

PTEN

SMAD4

TP53

FURTHER INFORMATION

The Jackson Laboratory

The p53 web site at L'Institut Curie

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Sieber, O., Heinimann, K. & Tomlinson, I. Genomic instability — the engine of tumorigenesis?. Nat Rev Cancer 3, 701–708 (2003). https://doi.org/10.1038/nrc1170

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