Germline and somatic mutations in exon 15 of the APC gene and K-ras mutations in duodenal adenomas in patients with familial adenomatous polyposis

Background: In sporadic colorectal adenomas mutations in the adenomatous po lyposis gene (APC) are among the first gene aberrations to appear. In famil ial adenomatous polyposis (FAP) the patients already have a germline mutati on in the APC gene. To investigate the natural history of duodenal adenomas in FAP patients, we examined germline and somatic mutations of the APC gen e and K-ras mutations in these lesions. Methods: Frozen sections from 54 du odenal polyps from 31 FAP patients were used to histologically verify the p resence of adenomatous growth in the mucosa; the rest of each biopsy specim en was processed for DNA extraction. APC exon 15 was investigated with the protein truncation test (PTT), using four overlapping polymerase chain reac tion (PCR) fragments, and samples showing an APC mutation were thereafter s equenced. The adenomas were examined for K-rns mutations by use of a combin ation of the 'enriched PCR method' and temporal temperature gradient electr ophoresis. Results: APC germline mutations in exon 15 were found in 19 of 3 1 (61%) patients, whereas somatic mutations were localized to 12 of 54 (22% ) duodenal adenomas. In seven adenomas both the germline and the somatic mu tations were found, whereas five small adenomas showed somatic mutations on ly. There was no tendency for more mutations to be detected in large and se verely dysplastic adenomas compared with small and mildly dysplastic ones. K-ras mutations were found in four (7%) duodenal adenomas. Conclusions: The low rate of somatic APC and K-ras mutations in duodenal adenomas may indic ate another neoplastic pathway than in FAP adenomas of the large bowel, or that a modifier gene is cosegregating with the disease.