Differing rates of loss of DPC4 expression and of p53 overexpression among carcinomas of the proximal and distal bile ducts.
BACKGROUND
Biliary tract carcinomas are clinically heterogeneous. It is not known if molecular heterogeneity underlies the clinical differences.


METHODS
The authors evaluated 128 bile duct carcinomas, 88 of the distal common bile duct and 40 of more proximal origin (28 perihilar carcinomas, 12 intrahepatic carcinomas), immunohistochemically for abnormalities in the expression of the products of the DPC4 and p53 tumor-suppressor genes. Prognostic factors were evaluated in the series of distal bile duct carcinomas for which follow-up information was available.


RESULTS
The authors found that a significantly higher percentage of distal bile duct carcinomas (55%) demonstrated loss of DPC4 expression than did the proximal bile duct carcinomas (15%; P < 0.001). They also found that a significantly higher percentage of the distal tumors abnormally expressed the p53 gene product (51% vs. 26%; P < 0.001). Among the distal common bile duct carcinomas, the presence of poorly differentiated histology correlated with decreased survival in multivariate analysis, while labeling for p53 or Dpc4, margin status, lymph node status, and tumor dimension did not correlate significantly with survival.


CONCLUSIONS
These results demonstrate that abnormalities in DPC4 and p53 gene expression are frequent in distal common bile duct carcinomas, just as they are in pancreatic ductal adenocarcinoma, suggesting that these two tumor types might share a similar molecular pathogenesis. They also show that proximal and distal bile duct carcinomas have different patterns of inactivation of tumor-suppressor genes, indicating that they often arise through different molecular mechanisms likely reflecting their differing etiologies.
Argani
P
P
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. pargani@jhmi.edu
Shaukat
A
A
Kaushal
M
M
Wilentz
R E
RE
Su
G H
GH
Sohn
T A
TA
Yeo
C J
CJ
Cameron
J L
JL
Kern
S E
SE
Hruban
R H
RH
D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D003138:Common Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D011379:Prognosis; D051901:Smad4 Protein; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53