Differential cell cycle-regulatory protein expression in biliary tract adenocarcinoma: Correlation with anatomic site, pathologic variables, and clinical outcome Journal Article


Authors: Jarnagin, W. R.; Klimstra, D. S.; Hezel, M.; Gonen, M.; Fong, Y.; Roggin, K.; Cymes, K.; DeMatteo, R. P.; D'Angelica, M.; Blumgart, L. H.; Singh, B.
Article Title: Differential cell cycle-regulatory protein expression in biliary tract adenocarcinoma: Correlation with anatomic site, pathologic variables, and clinical outcome
Abstract: Purpose: Biliary tract adenocarcinomas (BTAs), although anatomically related, arise through ill-defined and possibly different location-related pathogenetic pathways. This clinicopathologic study characterizes differences in cell cycle-regulatory protein expression across the spectrum of BTA. Methods: Tissue microarrays were prepared from paraffin-embedded surgical specimens with triplicate cores of BTA and benign tissue. Immunohistochemical expression of p53, cyclin D1, p21, Bcl2, p27, Mdm2, and Ki-67 was assessed, and the results were correlated with pathologic variables and survival. Hierarchical clustering was used to partition the data based on protein expression, and then the data were analyzed according to anatomic location. Results: Tissue from 128 surgical patients (1992 to 2002) was obtained. Tumor sites of origin were intrahepatic cholangiocarcinoma (IH; n = 23), hilar cholangiocarcinoma (Hilar; n = 54), gallbladder (GB; n = 32), and distal bile duct (Distal; n = 19). p27 expression decreased progressively from proximal to distal in the biliary tree and correlated with location-related differences in outcome; cyclin D1 and Bcl2 overexpression also varied according to anatomic site. Aberrant p53 staining and cyclin D1 overexpression were lower in papillary tumors compared with the more common sclerosing tumors. The expression profiles of GB and Hilar were more similar to each other than either was to IH or Distal (86% clustering in the first partition). After an R0 resection, overexpression of Mdm2 (P = .0062) and absent p27 expression (P = .0165) independently predicted poor outcome. Conclusion: BTAs differentially express cell cycle-regulatory proteins based on tumor location and morphology. Prognostic roles were identified for Mdm2 and p27. Overlap in the pathogenesis of GB and Hilar tumors was suggested. © 2006 by American Society of Clinical Oncology.
Keywords: immunohistochemistry; survival; adult; cancer survival; controlled study; human tissue; protein expression; aged; middle aged; survival analysis; major clinical study; cancer recurrence; outcome assessment; adenocarcinoma; ki 67 antigen; ki-67 antigen; cell cycle protein; cell cycle proteins; cell cycle; demography; protein bcl 2; neoplasm recurrence, local; cluster analysis; tumor markers, biological; pathology; protein p53; tumor marker; gene expression regulation; gene expression regulation, neoplastic; chemistry; tumor recurrence; protein p27; tumor suppressor protein p53; bile duct carcinoma; bile duct neoplasms; bile ducts, intrahepatic; cholangiocarcinoma; upregulation; papilloma; tissue microarray; cyclin dependent kinase inhibitor 1a; cyclin-dependent kinase inhibitor p21; cycline; up-regulation; gallbladder neoplasms; cyclin d1; protein p21; proto-oncogene proteins c-bcl-2; protein mdm2; proto-oncogene proteins c-mdm2; cdkn1a protein, human; proliferating cell nuclear antigen; bile duct tumor; gallbladder tumor; intrahepatic bile duct; p27 antigen
Journal Title: Journal of Clinical Oncology
Volume: 24
Issue: 7
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2006-03-01
Start Page: 1152
End Page: 1160
Language: English
DOI: 10.1200/jco.2005.04.6631
PUBMED: 16505435
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 36" - "Export Date: 4 June 2012" - "CODEN: JCOND" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Kevin King Roggin
    5 Roggin
  2. Leslie H Blumgart
    340 Blumgart
  3. Ronald P DeMatteo
    597 DeMatteo
  4. Bhuvanesh Singh
    206 Singh
  5. Mithat Gonen
    701 Gonen
  6. Karina Cymes
    5 Cymes
  7. David S Klimstra
    843 Klimstra
  8. William R Jarnagin
    583 Jarnagin
  9. Yuman Fong
    741 Fong
  10. Michael Hezel
    19 Hezel