The in vivo rate of somatic adenomatous polyposis coli mutation.
Cancer arises through successive somatic mutations/epimutations of oncogenes and tumor-suppressor genes. Accurate estimates of the rates at which these (epi)mutations occur are a vital but missing link in our emerging quantitative understanding of tumorigenesis. Their absence has hindered arguments concerning the importance of genetic instability in tumorigenesis and the number of mutations that precede malignant conversion of healthy cell lineages. Herein, a novel method for calculating the in vivo mutation rate of the adenomatous polyposis coli (APC) tumor-suppressor gene is presented. The large majority of bowel cancers are thought to be initiated by a partial loss of APC function, with the age-onset pattern dramatically altered for the worse in familial adenomatous polyposis (FAP) because these patients harbor selected germline APC mutations. Colon cancer in the context of FAP can be thought of as occurring "one hit quicker" than in the sporadic setting. We were able to isolate and estimate the rate of the initiating APC mutation in sporadic cases using the age incidence of FAP to approximate the time taken for a cell lineage in a sporadic patient with one APC mutation to present clinically as a cancer. Our result of approximately 10(-5) mutations per allele per year, although higher than previous estimates, appears to be consistent with the mutational spectrum of APC. The quality of fit provided by this method supports the theory that FAP and sporadic bowel cancer follow the same genetic pathway and are separated by only one mutation.
Hornsby
Chris
C
Department of Computer Science, University College London, London, U.K. c.hornsby@ucl.ac.uk
Page
Karen M
KM
Tomlinson
Ian
I
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D017677:Age Distribution; D000483:Alleles; D019070:Cell Lineage; D004848:Epithelium / Q000473:pathology; D006801:Humans; D009154:Mutation / Q000235:genetics*; D013234:Stem Cells / Q000473:pathology
D025601:Adenomatous Polyposis Coli Protein