The presence of chromosome 18q loss and DPC4 mutations in appendiceal adenocarcinomas suggests involvement of DPC4 and nearby genes on chromosome 18q (DCC and/or JV-18) in the pathogenesis of appendiceal adenocarcinomas.
These results suggest that carcinogenesis in the biliary tract epithelium in APBDU is accompanied by multistep genetic mutational events; K-ras gene mutation occurs early in epithelial hyperplasia or metaplasia, whereas inactivation of the DPC-4 gene accumulates late in the progression of biliary tract adenocarcinoma.
One hundred forty surgically resected ampullary adenocarcinomas (76 with associated adenomas with high-grade dysplasia) were immunohistochemically labeled for the DPC4 gene product, and in 85 cases the results were correlated with the status of the K-ras oncogene from previously reported data.
The frequency of loss of DPC4 expression was higher in poorly differentiated adenocarcinoma (G3) than in well and moderately differentiated adenocarcinoma (G1 and G2) histologically (P=0.037).
In a 12-year-old girl with adenocarcinoma arising from a choledochal cyst, K-ras and DPC-4 (homozygous deletion) mutations were identified simultaneously.
Patients with pancreatic adenocarcinomas with SMAD4 protein expression had significantly longer survival (unadjusted median survival was 19.2 months as compared with 14.7 months in patients with pancreatic cancers lacking SMAD4 protein expression; P = 0.03).
Specifically, DPC4 (deleted in pancreatic carcinoma, locus 4 or MADH4/SMAD4) is a tumor-suppressor gene mutated in approximately 50% of human pancreatic adenocarcinomas.
Immunohistochemical labeling revealed that 17 (94%) of the 18 primary adenocarcinomas with wild-type DPC4 genes expressed the DPC4 gene product, whereas 21 (91%) of 23 primary adenocarcinomas with inactivated DPC4 genes did not.
Recently, immunohistochemical labeling for the DPC4 gene product has been shown to be an extremely sensitive and specific marker for DPC4 gene alterations in pancreatic adenocarcinomas.
We recently inactivated its mouse homologue Smad4 and demonstrated its role in the malignant progression of benign adenomas to invasive adenocarcinomas by analyzing mice with Apc and Smad4 compound mutations.
Inactivation of the tumor suppressor gene DPC4 and other components of the TGF-beta signal cascades may abolish one of the key negative controls of cell proliferation in pancreatic adenocarcinomas.
We sought to determine whether Smad4 genetic alterations played a significant role in gastric tumorigenesis by studying 35 gastric adenocarcinomas of all histopathological types and pathological stages.