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Background-Germline mutation in the adenomatous polyposis coli (APC) gene on chromosome 5 causes familial adenomatous polyposis. "Attenuated" phenotype has been reported with mutation in the 5' end of the gene (5' to codon 158), but genotype-phenotype relations at the 3' end (3' to codon 1596) have not been described fully. Aims-To describe and compare colorectal and extracolonic phenotypes in a case series of families with mutation in the 3' end of the APC gene. Methods-Thirty one at risk or aVected members from four families with a mutation in the APC gene located at codon 1979 or 2644 were evaluated. Results-Variable intrapedigree colorectal phenotype was observed: some members at older age had oligopolyposis (fewer than one hundred colorectal adenomas) whereas other members had classic polyposis at young age. Colorectal cancer was diagnosed at older mean age (50 (7) years) in the four families than in classic FAP pedigrees (39 (14) years). Extracolonic lesions characteristic of FAP occurred with 3' APC mutations, but variability in intrapedigree and interpedigree extracolonic phenotype and dissociation of severity of extracolonic manifestations from number of colorectal polyps was noted. Conclusions-Families with 3' mutations of the APC gene exhibit variable intrapedigree phenotype similar to the heterogeneity noted in families with proximal 5' mutations. Genotyping of FAP and oligopolyposis pedigrees can guide appropriate surveillance of the upper and lower gastrointestinal tract in aVected members. (Gut 1998;43:548-552)

The rat model of azoxymethane (AOM) induced colonic carcinogenesis was evaluated for preneoplastic changes in epithelial DNA synthesis and histopathologic characteristics analogous to those observed in human beings at high risk for colonic carcinoma. 10-week-old male Fischer 344 rats were given 10 weekly subcutaneous injections of AOM at a dose of 15 mg/kg. Every 2 weeks after the first carcinogen dose, 5 animals were sacrificed 1 h after an intraperitoneal injection of methyl-³thymidine, 0.5 mCi/kg body weight. The experiment was terminated 25 weeks after the first AOM injection. By autoradiography, the labelling index (LI) of the ascending colon (AC) was 8.6 ± 0.5 % for AOM-treated animals and 4.7 ± 0.94% for controls (p < 0.05). In the descending colon (DLC) the LI was 10.3 ± 0.9% for AOM-treated animals as compared to 6.8 ± 1.4% for controls (p < 0.01). In the AC the main zone of DNA synthesis shifted from the lower third to the middle third of the crypt in AOM-treated rats, while in the DLC the zone remained in the basal third. No crypt epithelial hyperplasia was found with carcinogen treatment. Crypt elongation, crypt dilatation, and mucosal edema formation were associated with the course of AOM administration and appeared to be toxic effects. In contrast, the mucus content of the crypt epithelium showed a biphasic decrease over the entire time course of the study. Dysplastic crypts appeared earlier in the AC, however, and the early appearance was associated with persistently elevated labelling indices and shift in the main zone of DNA synthesis. We conclude that in experimental colonic carcinogenesis, preneoplastic changes in cell proliferation (‘stage I’ and ‘stage IF abnormalities) similar to those in human beings at high risk can be observed. Thus, despite the absence of an adenoma-carcinoma sequence, experimental colonic carcinogenesis provides an important model to study modulators of preneoplastic changes and their impact on malignant transformation of colonic mucosa.

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