S1083 Uncomplicated Peptic Ulcer in the UK: Trends from 1997 to 2005

Abstract

Background: The duodenal adenomas as seen in familial adenomatous polyposis (FAP) are likely to develop through the classical adenoma-carcinoma pathway as they exhibit mutations in the APC gene, KRAS mutations, p53 dysfunction, and loss of E-cadherin expression. However, it is unknown whether sporadic duodenal adenomas also develop into duodenal carcinoma through the classical adenoma carcinoma sequence. Limited data suggest that sporadic adenomas show similar molecular features as colorectal adenomas, harboring APC and KRAS mutations. Therefore, the aim of the present study was to evaluate the molecular changes of sporadic duodenal adenomas. Methods: Tissue samples of 64 sporadic duodenal adenomas were available from the pathology archives of two academic hospitals. Tissue samples of patients with duodenal carcinoma or patients with FAP were excluded. None of the patients belonged to a known Lynch syndrome family. DNA was extracted from paraffin sections of the adenoma and analyzed for the presence of microsatellite instability. Also, mutation analysis using polymerase chain reaction followed by direct-sequencing was performed. The mutation analysis included mutational hotspots of the Wnt signaling pathway (APC, β-catenin), the MAP kinase pathway (KRAS and BRAF) and the del1100c mutation within the CHK2 gene. Results: Two (3%) of the 64 adenomas showed a high level of MSI (MSI-H). APC mutation analysis was possible in 52 adenomas and revealed a mutation in thirteen (24%), including seven duodenal adenomas with a recurrent 4684insA (K1555fsX1557)mutation. KRASmutation analysis was possible in 52 adenomas and revealed one (2%) mutation (34GGT>TGT (G12C)). β-catenin mutation analysis was possible in 48 adenomas and revealed one (2%) mutation (121ACC>GCC(T41A)). BRAF (58 adenomas) and CHK2 (53 adenomas) mutation analysis did not reveal any mutation. Conclusions: In our cohort of sporadic duodenal adenomas the frequency of Wnt signaling pathway abnormalities is low, most adenomas are microsatellite stable and the number of MAP kinase pathway abnormalities is negligible. In addition, CHK2 mutations seem not to be present in sporadic duodenal adenomas. These findings suggest that a proportion of sporadic duodenal adenomas develop via the same mechanisms (the adenoma-carcinoma sequence) as colorectal adenomas, but it is possible that other molecular changes may also underlie the development of sporadic duodenal adenomas.