Evolutionary dynamics of tumor suppressor gene inactivation
- *Program for Evolutionary Dynamics and Departments of †Organismic and Evolutionary Biology and ‡Mathematics, Harvard University, Cambridge, MA 02138; ¶Department of Mathematics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; and ∥Department of Biology, Kyushu University, Fukuoka 812-8581, Japan
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Edited by George Klein, Karolinska Institutet, Stockholm, Sweden, and approved May 27, 2004 (received for review February 3, 2004)
Abstract
Tumor suppressor genes (TSGs) are important gatekeepers that protect against somatic evolution of cancer. Losing both alleles of a TSG in a single cell represents a step toward cancer. We study how the kinetics of TSG inactivation depends on the population size of cells and the mutation rates for the first and second hit. We calculate the probability as function of time that at least one cell has been generated with two inactivated alleles of a TSG. We find three different kinetic laws: in small, intermediate, and large populations, it takes, respectively, two, one, and zero rate-limiting steps to inactivate a TSG. We also study the effect of chromosomal and other genetic instabilities. Small lesions without genetic instability can take a very long time to inactivate the next TSG, whereas the same lesions with genetic instability pose a much greater risk for cancer progression.
Footnotes
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↵ § To whom correspondence should be addressed. E-mail: martin_nowak{at}harvard.edu.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: TSG, tumor suppressor gene; CIN, chromosomal instability; MIN, microsatellite instability.
- Copyright © 2004, The National Academy of Sciences
