These results suggest the following mechanisms for the development of colon tumors in patients with familial adenomatous polyposis: (a) the heterozygous mutant/wild-type condition at the APC gene causes formation of mild or moderate adenoma; (b) the loss of the normal allele in the APC gene leads to a change from moderate to severe adenoma; (c) LOH on chromosome 17p contributes to the conversion of adenoma to intramucosal carcinoma; (d) LOH on other chromosomes, such as 18 and 22q, are involved in the progression of intramucosal carcinoma to invasive carcinoma; and (e) K-ras mutation may also affect the development of moderate to severe adenoma.
We determined the genomic structure of the rat Apc gene, and we analyzed mutations in colon tumors induced in F344 rats by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), potent carcinogens contained in ordinary daily human food.
Our results support the view that malignant progression is a consequence of more than one genetic change and suggest that inactivation of APC and DCC genes plays a role in a multistep process of colon tumor progression.
Recent evidence suggests that the beta-catenin gene (CTNNB1) acts as an oncogene, and some human colon tumors with an intact APC gene have activating mutations in CTNNB1.
Neonatal exposure to the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine via breast milk or directly induces intestinal tumors in multiple intestinal neoplasia mice.
One dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) induces tumours in Min/+ mice by truncation mutations or LOH in the Apc gene.
We determined the error spectrum of DNA polymerase beta in the human APC gene under PCR conditions and compared it with the set of mutations reported in human colon tumors.
To study the role of APC in signaling ODC expression, we used the human colon tumor cell line HT29 (wtAPC-/-), which has been stably transfected with a zinc-inducible wild-type APC gene.
The different pathways observed and their distribution can be summarized as follows: (a) K-ras mutations were more commonly detected in colon than in rectum; (b) the number of mutations detected was significantly higher in colon than in rectal tumors; and (c) a mutational pattern restricted to the APC gene was more common in rectal than in colon tumors.
Tumor suppressor APC blocks DNA polymerase beta-dependent strand displacement synthesis during long patch but not short patch base excision repair and increases sensitivity to methylmethane sulfonate.
From this descriptive study, it seems that the short-term risk for colonic polyps in I1307KAPC mutation is low, primarily affecting patients with previously diagnosed colon tumors.
Total meat consumption was not associated with the endpoints studied.Meat product (i.e. processed meat) consumption showed a positive association with colon tumours harbouring a truncating APC mutation, whereas beef consumption was associated with an increased risk of colon tumours without a truncating APC mutation (incidence rate ratio (RR) highest versus lowest quartile of intake 1.61, 95% confidence interval (CI) 0.96-2.71, p-trend = 0.04 and 1.58, 95% CI 1.10-2.25, p-trend = 0.01, respectively).
The majority of colon tumors develop because of mutations in the tumor suppressor APC that lead to Wnt/beta-catenin signaling activation and subsequent transcription of target genes, including conductin/AXIN2.
Relatively high folate consumption reduced the risk of APC(-) colon tumors, but folate intake was positively associated with APC(+) colon tumors among men.