Dynamics of genetic instability in sporadic and familial colorectal cancer.
Genetic instability is a defining feature of human cancer. In colorectal cancer, two specific types of genetic instabilities have been identified: microsatellite instability (MIN) leads to a 1000-fold increase in the rate of subtle DNA changes, whereas chromosomal instability (CIN) enhances the rate at which gross chromosomal changes occur during cell division. In this paper, we develop a mathematical model for the dynamics of colon cancer initiation. We outline the processes and rate constants that determine the fraction of colon cancers where MIN or CIN mutations precede the inactivation of the first tumor suppressor gene. For a wide range of parameter values, we find support for the radical hypothesis that genetic instability initiates colonic tumorigenesis. We compare sporadic and hereditary forms of colorectal cancer.
Komarova
Natalia L
NL
Institute for Advanced Study, Princeton, New Jersey, USA. natalia@ias.edu
Lengauer
Christoph
C
Vogelstein
Bert
B
Nowak
Martin A
MA
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D002455:Cell Division; D002869:Chromosome Aberrations; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D008962:Models, Theoretical; D009154:Mutation