Selection, the mutation rate and cancer: ensuring that the tail does not wag the dog

ABSTRACT IN CONSIDERING TUMORIGENESIS, MUCH ATTENTION IS PAID TO GENOME INSTABILITY AND MUTATION RATES. WHILE REFLECTING ON THE CIRCUMSTANCES THAT HAVE LED TO THIS EMPHASIS ON MUTATION

RATES, IAN TOMLINSON AND WALTER BODMER POINT OUT THAT AN INCREASED MUTATION RATE DOES NOT NECESSARILY CAUSE A TUMOR TO GROW AND THAT SELECTION IS IN FACT THE MECHANISM THAT DRIVES THE

CELLULAR, SOMATIC EVOLUTION THAT LEADS TO CANCER. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

Access through your institution Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on

SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about

institutional subscriptions * Read our FAQs * Contact customer support REFERENCES * Brugarolas, J. & Jacks, T. Double indemnity: p53, BRCA and cancer. _Nature Med._ 3, 721–722 (1997).

Article  CAS  Google Scholar  * Cairns, J. Mutation and cancer: the antecedents to our studies of adaptive mutation. _Genetics_ 148, 1433–1440 (1998). CAS  PubMed  PubMed Central  Google

Scholar  * Kinzler, K.W. & Vogelstein, B.V. Lessons from hereditary colorectal cancer. _Cell_ 87, 159–170 (1996). Article  CAS  Google Scholar  * Rotman, G. & Shiloh, Y. ATM: from

gene to function. _Hum. Mol. Genet_. 7, 1555–1563 (1998). Article  CAS  Google Scholar  * Loeb, L.A., C.F. Springgate & Battula, N. Errors in DNA replication as a basis of malignant

changes. _Cancer Res_. 34, 2311–2321 (1974). CAS  PubMed  Google Scholar  * Loeb, L.A. . Transient expression of a mutator phenotype in cancer cells. _Science_ 277, 1449–1450 (1997). Article

  CAS  Google Scholar  * Cairns, J. Mutation selection and the natural history of cancer. _Nature_ 255, 197–200 (1975). Article  CAS  Google Scholar  * Tomlinson, I.P.M., M.R. Novelli &

Bodmer, W.F. The mutation rate and cancer. _Proc. Natl. Acad. Sci. USA_ 93, 14800–14803 (1996). Article  CAS  Google Scholar  * Homfray, T.F.R. et al. Defects in mismatch repair occur after

APC mutations in the pathogenesis of sporadic colorectal tumors. _Hum. Mutat_. 11, 114–120 (1998). Article  CAS  Google Scholar  * Huang, J. et al. APC mutations in colorectal tumors with

mismatch repair deficiency. _Proc. Natl. Acad. Sci. USA_ 93, 9049–9054 (1996). Article  CAS  Google Scholar  * Nowell, P.C. The clonal evolution of tumor cell populations. _Science_ 194,

23–28 (1976). Article  CAS  Google Scholar  * Orr–Weaver, T.L. & Weinberg, R.A. A checkpoint on the road to cancer. _Nature_ 392, 223–224 (1998). Article  Google Scholar  * Loeb, L.A.

Mutator phenotype may be required for multistage carcinogenesis. _Cancer Res_. 51, 3075–3079 (1991). CAS  PubMed  Google Scholar  * Tomlinson, I.P.M. & Bodmer, W.F. . Failure of

programmed cell death and differentiation as causes of tumors: some simple mathematical models. _Proc. Natl. Acad. Sci. USA_ 92, 11130–11134 (1995). Article  CAS  Google Scholar  * Richards,

B. et al. Conditional mutator phenotypes in hMSH2–deficient tumor cell lines. _Science_ 277, 1523–1525 (1997). Article  CAS  Google Scholar  * Branch, P. et al. Immune surveillance in

colorectal carcinoma. _Nature Genet_. 9, 231–232 (1995). Article  CAS  Google Scholar  * Young, J. et al. Genomic instability occurs in colorectal carcinomas but not in adenomas. _Hum.

Mutat_. 2, 351–354 (1993). Article  CAS  Google Scholar  * Davis, T.W. et al. Defective expression of the DNA mismatch repair protein, MLH1, alters G2–M cell cycle checkpoint arrest

following ionizing radiation. _Cancer Res._ 58, 767–768 (1998). CAS  PubMed  Google Scholar  * Kinzler, K.W. & Vogelstein, B. Cancer–susceptibility genes. Gatekeepers and caretakers.

_Nature_ 386, 761–763 (1997). Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Molecular and Population Genetics Laboratory, Imperial Cancer

Research Fund, 44, Lincoln's Inn Fields, London, WC2A 3PX, UK Ian Tomlinson * Cancer and Immunogenetics Laboratory, Imperial Cancer Research Fund, Institute of Molecular Medicine, John

Radcliffe Hospital, Oxford, OX3 9DZ, UK Walter Bodmer Authors * Ian Tomlinson View author publications You can also search for this author inPubMed Google Scholar * Walter Bodmer View author

publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Tomlinson, I., Bodmer, W.

Selection, the mutation rate and cancer: Ensuring that the tail does not wag the dog. _Nat Med_ 5, 11–12 (1999). https://doi.org/10.1038/4687 Download citation * Issue Date: January 1999 *

DOI: https://doi.org/10.1038/4687 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently

available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative