Purpose: The DPC4/Smad4 gene is known to perform a key role in the
TGF-β group protein signaling pathway, which regulates cell proliferation,
differentiation and death. DPC4/ Smad4 gene mutation has been studied in
cancers of the breast, ovary, esophagus, colo-rectum, bile duct, as well as
the pancreas. The mutation rates depend on the kind of carcinoma sites, and
range from 10% to around 50%, but no study has been performed on gallbladder
carcinomas. This study was performed to search for mutation of the
DPC4/Smad4 gene in the gallbladder carcinomas. Methods: Eighteen
surgically resected gallbladder cancers were screened for mutation of the
exons; 8, 9, 10 and 11 of the DPC4/Smad4 gene using dideoxyfingerprinting
(ddF), and single strand conformational polymorphism (SSCP). The results
were confirmed using automatic DNA sequencing, and the expressions examined
by immunohistochemical staining with the monoclonal anti-DPC4/Smad4 protein
antibody, B8. Results: DdF revealed 3 mutations in two of the exons,
which were confirmed by direct sequencing. In one case, a single-base
substitution mutation existed in exon 11 with codon change (missense
mutation), whereas in two cases such mutations were detected in exon 9
without codon change (silent mutation). Immunohistochemical staining showed
negative to weakly positive expression for all three mutated cases, but had
high false-positive rates (7/11). Conclusion: DPC4/Smad4 gene
mutation exists in a certain proportion of gallbladder carcinomas, but the
mutation rate seems to be low compared to organogenetically related pancreas
or bile duct carcinomas. This suggests somewhat different mechanisms may
operate on the carcinogenesis of these organs.
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