Mutations in APC, Kirsten-ras, and p53--alternative genetic pathways to colorectal cancer.
Colorectal cancer is one of the most significant causes of cancer death. A genetic model for colorectal cancer has been proposed in which the sequential accumulation of mutations in specific genes, including adenomatous polyposis coli (APC), Kirsten-ras (K-ras), and p53, drives the transition from healthy colonic epithelia through increasingly dysplastic adenoma to colorectal cancer. We have characterized tumor mutation spectra in a large cohort of colorectal cancer patients. In marked contrast to the predictions of the sequential model of mutation accumulation, only 6.6% of tumors were found to contain mutations in APC, K-ras, and p53, with 38.7% of tumors containing mutations in only one of these genes. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and K-ras were extremely rare. Statistical analysis (two-sided Fisher's exact test) confirmed that mutations in K-ras and p53 co-occurred less frequently than expected by chance (P < 0.01, Fisher's exact test). This finding suggests that these mutations lie on alternate pathways of colorectal tumor development. The heterogeneous pattern of tumor mutations in our patient cohort suggests that multiple alternative genetic pathways to colorectal cancer exist and that the widely accepted genetic model of cancer development is not representative of the majority of colorectal tumors.
Smith
Gillian
G
Cancer Research United Kingdom Molecular Pharmacology Unit, Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.
Carey
Francis A
FA
Beattie
Julie
J
Wilkie
Murray J V
MJ
Lightfoot
Tracy J
TJ
Coxhead
Jonathan
J
Garner
R Colin
RC
Steele
Robert J C
RJ
Wolf
C Roland
CR
D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D017491:Genes, APC; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation