No abstract

Summary Whether duodenal adenocarcinoma should be considered as a gastrointestinal or as a peripancreatic cancer is a matter of debate, as is the opportunity and type of treatment. We investigated 12 such cancers for the genetic anomalies involved in the pathogenesis of gastrointestinal malignancies, including (a) those occurring in common-type cancers -allelic losses at chromosomes 3p, 5q, 1 7p and 1 8q, and Ki-ras and p53 alterations; and (b) those characteristic of mutator-phenotype cancers -microsatellite instability and TGF-PRII gene mutations. We found Ki-ras and p53 mutations in five (42%) and eight cancers (67%), respectively; chromosome 3p, 5q, 1 7p and 1 8q allelic losses in two of nine (22%), six of ten (60%), six of nine (67%) and three of ten (30%) informative cancers, respectively. Finally, three cancers (25%) showed widespread microsatellite instability and two of them had a TGF-pRII gene mutation. Our data suggest that duodenal cancers may arise from either of the two known pathogenetic molecular pathways of gastric and colorectal cancers. The majority of our cases were highly aggressive cancers with frequent chromosomal changes and p53 mutations as observed in the common-type gastrointestinal malignancies, while widespread subtle alterations characteristic of mutator-phenotype cancers occurred in a minority, which also showed a favourable long-term outcome.

Summary During our studies of DNA fingerprinting of tumours of the pancreas and papilla (ampulla) of Vater, using arbitrarily primed polymerase chain reaction (AP-PCR), we noticed two bands showing a decreased intensity in six of ten ampullary tumours with respect to matched normal tissues. Those bands were both assigned to chromosome 5. Such a finding was somewhat in contrast with the reportedly low frequency of APC gene mutations in ampullary cancers, located at chromosome 5q21, and suggested that loci different from that of APC might be the target of chromosome 5 allelic losses (LOH) in these tumours. Therefore, we analysed chromosome 5 LOH in a panel of 27 ampullary tumours, including eight adenomas, four earty-and 15 advanced-stage cancers, using 16 PCR-amplified CA microsatellite polymorphic markers spanning the entire chromosome. Nineteen cases (70%/a) showed LOH, and the interstital deletions found in these tumours described two smallest common deleted regions, in which putative suppressor genes might reside. They were at 5q13.3-q14 and at 5q23-q31 respectively, which correspond to those found in gastic tumours. In additon, the presence of 5q LOH in six of eight adenomas and in three of four earty-stage cancers suggests that such phenomena occur at earty stages of neoplastic progression of the ampullary epithelium.

Mutations in the first and second exons of Ha-, Ki- and N-ras oncogenes were investigated in 17 epithelial tumors of the ampulla of Vater by single-strand conformation polymorphism analysis and direct sequencing of DNA fragments amplified by polymerase chain reaction. The panel included 12 intestinal-type adenocarcinomas, 3 villous adenomas, 1 papillary carcinoma and 1 neuroendocrine carcinoma. Six cases (35%) contained ras mutations, affecting codon 12 of Ki-ras in 2 adenomas and 3 carcinomas, and of N-ras in 1 adenoma. All mutations were found in adenomas and among cancers with adenomatous areas, whereas none of the cases lacking adenomatous areas contained mutations. This suggested that ampullary cancers represent heterogeneous diseases with respect to the presence or absence of adenomatous areas and, among those with adenomatous areas, with respect to the presence of activated ras genes. Ki-ras mutated cases included 3 of 4 tumors which mainly involved the intraduodenal bile duct, thus suggesting that a proportion of Ki-ras-mutated ampullary cancers might correspond to those originating from the epithelium of the bile duct component of the ampulla.

We explored APC gene mutations and chromosome 5q21 allelic losses (5qLOH) in 18 neoplasms of the papilla of Vater, including 6 early-stage tumours (3 adenomas, 3 carcinomas) and I 2 advanced-stage cancers. Eleven PCR-amplified polymorphic sequences were used to analyse 5qLOH. AfK mutations were investigated both by an In vitro APC-protein truncation test and by single-strand conformation polymorphism analysis. Mutations in the Ki-ras, N-ras and p53 genes were also assessed. We found: 5qLOH in 8 of 16 cases (50%), including I adenoma. 3 early-and 4 advanced-stage cancers; APC mutations in 2 adenomas and I advanced-stage carcinoma; Ki-or N-ras mutations in 3 adenomas and 3 advanced-stage cancers; pS3 mutations in 2 early-stage and 7 advanced-stage adenocarcinomas. Our results suggest that SqLOH, APC mutations and ras mutations are present at early stages, whereas p53 inactivation is associated with progression of malignancy in a large proportion of cases. These data indicate that sporadic ampullary tumours differ from those occurring in familial adenomatous polyposis in the frequency (I 7% vs. 64Oh) as well as in the site of APC somatic mutations, suggesting a different molecular pathogenesis in the 2 conditions. cri 1906 Wilq-Liss, Inc.Ampullary epithelial neoplasms include benign (5%) and malignant tumours (95%) centered in the region of the papilla of Vater. They represent 5% of all sporadic gastrointestinal tumours, but account for up to 36% of the surgically operable pancreatoduodenal tumours, whereas sporadic duodenal neoplasms not originating from ampullary structures arc exccedingly rare. Ampullary and duodenal non-ampullary neoplasms occur at a high frequency in patients affected by familial adenomatous polyposis (FAP) (reviewed in Gallinger et a/.,