| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Short Communications |
From the Departments of Pathology,*
Oncology,
and
Surgery,
The Johns Hopkins Medical
Institutions, Baltimore, Maryland
DPC4 (MADH4, SMAD4) is a tumor suppressor gene inactivated by allelic loss in approximately 55% of pancreatic adenocarcinomas. Unfortunately, it can be technically very difficult to detect the inactivation of DPC4 at the genetic level because genetic analyses require the microdissection of relatively pure samples of neoplastic and normal tissues. This is especially true for pancreatic adenocarcinomas, which elicit vigorous, non-neoplastic, stromal responses. Immunohistochemical labeling can overcome this hurdle because it preserves morphological information. We therefore studied the expression of the DPC4 gene product in 46 cancers, including 5 cancer cell lines by Western blot analysis and 41 primary periampullary adenocarcinomas by immunohistochemistry. The status of exons 1–11 of the DPC4 gene in all 46 of the cancers had been previously characterized at the molecular level, allowing us to correlate Dpc4 expression directly with gene status. Three cell lines had wild-type DPC4 genes, and Dpc4 expression was detected in all three by Western blot. The two cell lines with homozygously deleted DPC4 genes did not show Dpc4 protein by Western blot analysis. 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. Cases in which there was discordance between the immunohistochemical labeling and the genetic analyses were reanalyzed genetically, and we identified a deletion in exon 0 of DPC4 in one of these cases. This is the first report of a mutation in exon 0 of DPC4 in a pancreatic cancer. The contrast between the strong expression of Dpc4 by normal tissues and the loss of expression in the carcinomas was highlighted in several cases in which an infiltrating cancer was identified growing into a benign duct. These observations suggest that immunohistochemical labeling for the DPC4 gene product is an extremely sensitive and specific marker for DPC4 gene alterations in pancreatic carcinomas. The sensitivity and specificity of immunohistochemical labeling for Dpc4 in other periampullary carcinomas has yet to be determined.
This article has been cited by other articles:
 |
|
 |
|
  J. R. Infante, H. Matsubayashi, N. Sato, J. Tonascia, A. P. Klein, T. A. Riall, C. Yeo, C. Iacobuzio-Donahue, and M. Goggins Peritumoral Fibroblast SPARC Expression and Patient Outcome With Resectable Pancreatic Adenocarcinoma J. Clin. Oncol., January 20, 2007; 25(3): 319 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Alhopuro, H. Alazzouzi, H. Sammalkorpi, V. Davalos, R. Salovaara, A. Hemminki, H. Jarvinen, J.-P. Mecklin, S. Schwartz Jr., L. A. Aaltonen, et al. SMAD4 Levels and Response to 5-Fluorouracil in Colorectal Cancer Clin. Cancer Res., September 1, 2005; 11(17): 6311 - 6316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Vimalachandran, W. Greenhalf, C. Thompson, J. Luttges, W. Prime, F. Campbell, A. Dodson, R. Watson, T. Crnogorac-Jurcevic, N. Lemoine, et al. High Nuclear S100A6 (Calcyclin) Is Significantly Associated with Poor Survival in Pancreatic Cancer Patients Cancer Res., April 15, 2005; 65(8): 3218 - 3225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Alazzouzi, P. Alhopuro, R. Salovaara, H. Sammalkorpi, H. Jarvinen, J.-P. Mecklin, A. Hemminki, S. Schwartz Jr., L. A. Aaltonen, and D. Arango SMAD4 as a Prognostic Marker in Colorectal Cancer Clin. Cancer Res., April 1, 2005; 11(7): 2606 - 2611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Takahashi, T. Oda, T. Hasebe, Y. Aoyagi, T. Kinoshita, M. Konishi, T. Nakagohri, K. Inoue, S. Takahashi, H. Kawahira, et al. Biologically Different Subgroups of Invasive Ductal Carcinoma of the Pancreas: Dpc4 Status According to the Ratio of Intraductal Carcinoma Components Clin. Cancer Res., June 1, 2004; 10(11): 3772 - 3779. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. H. Kim, H. S. Lee, H.-J. Lee, K. Hur, W. H. Kim, Y.-J. Bang, S.-J. Kim, K. U. Lee, K. J. Choe, and H.-K. Yang Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas Ann. Onc., April 1, 2004; 15(4): 574 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Iacobuzio-Donahue, J. Song, G. Parmiagiani, C. J. Yeo, R. H. Hruban, and S. E. Kern Missense Mutations of MADH4: Characterization of the Mutational Hot Spot and Functional Consequences in Human Tumors Clin. Cancer Res., March 1, 2004; 10(5): 1597 - 1604. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Svrcek, F Jourdan, N Sebbagh, A Couvelard, D Chatelain, N Mourra, S Olschwang, D Wendum, and J-F Flejou Immunohistochemical analysis of adenocarcinoma of the small intestine: a tissue microarray study J. Clin. Pathol., December 1, 2003; 56(12): 898 - 903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. van der Heijden, R. H. Hruban, and S. E. Kern Reply Cancer Res., October 15, 2003; 63(20): 6999 - 7001. [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. House, M. Guo, C. Iacobuzio-Donahue, and J. G. Herman Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas Carcinogenesis, February 1, 2003; 24(2): 193 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Salovaara, S Roth, A Loukola, V Launonen, P Sistonen, E Avizienyte, P Kristo, H Jarvinen, S Souchelnytskyi, M Sarlomo-Rikala, et al. Frequent loss of SMAD4/DPC4 protein in colorectal cancers Mol. Pathol., December 1, 2002; 55(6): 385 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Biankin, A. L. Morey, C.-S. Lee, J. G. Kench, S. A. Biankin, H. C. Hook, D. R. Head, T. B. Hugh, R. L. Sutherland, and S. M. Henshall DPC4/Smad4 Expression and Outcome in Pancreatic Ductal Adenocarcinoma J. Clin. Oncol., December 1, 2002; 20(23): 4531 - 4542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Peng, J. B. Fleming, T. Breslin, A. M. Grau, S. Fojioka, J. L. Abbruzzese, D. B. Evans, D. Ayers, K. Wathen, T. Wu, et al. Suppression of Tumorigenesis and Induction of p15ink4b by Smad4/DPC4 in Human Pancreatic Cancer Cells Clin. Cancer Res., November 1, 2002; 8(11): 3628 - 3638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. P. van Rees, E. Caspers, A. zur Hausen, A. van den Brule, P. Drillenburg, M. A. J. Weterman, and G. J. A. Offerhaus Different Pattern of Allelic Loss in Epstein-Barr Virus-Positive Gastric Cancer with Emphasis on the p53 Tumor Suppressor Pathway Am. J. Pathol., October 1, 2002; 161(4): 1207 - 1213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Salovaara, S Roth, A Loukola, V Launonen, P Sistonen, E Avizienyte, P Kristo, H Jarvinen, S Souchelnytskyi, M Sarlomo-Rikala, et al. Frequent loss of SMAD4/DPC4 protein in colorectal cancers Gut, July 1, 2002; 51(1): 56 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A V Biankin, S A Biankin, J G Kench, A L Morey, C-S Lee, D R Head, R P Eckstein, T B Hugh, S M Henshall, and R L Sutherland Aberrant p16INK4A and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma Gut, June 1, 2002; 50(6): 861 - 868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Abraham, D. S. Klimstra, R. E. Wilentz, C. J. Yeo, K. Conlon, M. Brennan, J. L. Cameron, T.-T. Wu, and R. H. Hruban Solid-Pseudopapillary Tumors of the Pancreas Are Genetically Distinct from Pancreatic Ductal Adenocarcinomas and Almost Always Harbor {beta}-catenin Mutations Am. J. Pathol., April 1, 2002; 160(4): 1361 - 1369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Abraham, T.-T. Wu, R. H. Hruban, J.-H. Lee, C. J. Yeo, K. Conlon, M. Brennan, J. L. Cameron, and D. S. Klimstra Genetic and Immunohistochemical Analysis of Pancreatic Acinar Cell Carcinoma : Frequent Allelic Loss on Chromosome 11p and Alterations in the APC/{beta}-Catenin Pathway Am. J. Pathol., March 1, 2002; 160(3): 953 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Xie, J. C. Mertens, D. J. Reiss, D. L. Rimm, R. L. Camp, B. G. Haffty, and M. Reiss Alterations of Smad Signaling in Human Breast Carcinoma Are Associated with Poor Outcome: A Tissue Microarray Study Cancer Res., January 1, 2002; 62(2): 497 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Biankin, J. G. Kench, A. L. Morey, C.-S. Lee, S. A. Biankin, D. R. Head, T. B. Hugh, S. M. Henshall, and R. L. Sutherland Overexpression of p21WAF1/CIP1 is an Early Event in the Development of Pancreatic Intraepithelial Neoplasia Cancer Res., December 1, 2001; 61(24): 8830 - 8837. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sato, C. Rosty, M. Jansen, N. Fukushima, T. Ueki, C. J. Yeo, J. L. Cameron, C. A. Iacobuzio-Donahue, R. H. Hruban, and M. Goggins STK11/LKB1 Peutz-Jeghers Gene Inactivation in Intraductal Papillary-Mucinous Neoplasms of the Pancreas Am. J. Pathol., December 1, 2001; 159(6): 2017 - 2022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Tascilar, H. G. Skinner, C. Rosty, T. Sohn, R. E. Wilentz, G. J. A. Offerhaus, V. Adsay, R. A. Abrams, J. L. Cameron, S. E. Kern, et al. The SMAD4 Protein and Prognosis of Pancreatic Ductal Adenocarcinoma Clin. Cancer Res., December 1, 2001; 7(12): 4115 - 4121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Maurice, C. E. Pierreux, M. Howell, R. E. Wilentz, M. J. Owen, and C. S. Hill Loss of Smad4 Function in Pancreatic Tumors. C-TERMINAL TRUNCATION LEADS TO DECREASED STABILITY J. Biol. Chem., November 9, 2001; 276(46): 43175 - 43181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Woodford-Richens, A. J. Rowan, R. Poulsom, S. Bevan, R. Salovaara, L. A. Aaltonen, R. S. Houlston, N. A. Wright, and I. P. M. Tomlinson Comprehensive Analysis of SMAD4 Mutations and Protein Expression in Juvenile Polyposis : Evidence for a Distinct Genetic Pathway and Polyp Morphology in SMAD4 Mutation Carriers Am. J. Pathol., October 1, 2001; 159(4): 1293 - 1300. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. L. Woodford-Richens, A. J. Rowan, P. Gorman, S. Halford, D. C. Bicknell, H. S. Wasan, R. R. Roylance, W. F. Bodmer, and I. P. M. Tomlinson SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway PNAS, July 24, 2001; (2001) 171321498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Lassus, R. Salovaara, L. A. Aaltonen, and R. Butzow Allelic Analysis of Serous Ovarian Carcinoma Reveals Two Putative Tumor Suppressor Loci at 18q22-q23 Distal to SMAD4, SMAD2, and DCC Am. J. Pathol., July 1, 2001; 159(1): 35 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Wilentz, P. Argani, and R. H. Hruban Loss of Heterozygosity or Intragenic Mutation, Which Comes First? Am. J. Pathol., May 1, 2001; 158(5): 1561 - 1563. [Full Text] [PDF]
|
|
|
|
|
|
J. Luttges, H. Galehdari, V. Brocker, I. Schwarte-Waldhoff, D. Henne-Bruns, G. Kloppel, W. Schmiegel, and S. A. Hahn Allelic Loss Is Often the First Hit in the Biallelic Inactivation of the p53 and DPC4 Genes During Pancreatic Carcinogenesis Am. J. Pathol., May 1, 2001; 158(5): 1677 - 1683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. H. Su, R. Bansal, K. M. Murphy, E. Montgomery, C. J. Yeo, R. H. Hruban, and S. E. Kern ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma PNAS, March 13, 2001; 98(6): 3254 - 3257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M M Entius, J J Keller, A M Westerman, B P van Rees, M-L F van Velthuysen, A F P M de Goeij, J H P Wilson, F M Giardiello, and G J A Offerhaus Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome J. Clin. Pathol., February 1, 2001; 54(2): 126 - 131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Montgomery, M. Goggins, S. Zhou, P. Argani, R. E. Wilentz, M. Kaushal, S. Booker, K. Romans, P. Bhargava, R. H. Hruban, et al. Nuclear Localization of Dpc4 (Madh4, Smad4) in Colorectal Carcinomas and Relation to Mismatch Repair/Transforming Growth Factor-{beta} Receptor Defects Am. J. Pathol., February 1, 2001; 158(2): 537 - 542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Maitra, K. Molberg, J. Albores-Saavedra, and G. Lindberg Loss of Dpc4 Expression in Colonic Adenocarcinomas Correlates with the Presence of Metastatic Disease Am. J. Pathol., October 1, 2000; 157(4): 1105 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Iacobuzio-Donahue, D. S. Klimstra, N. V. Adsay, R. E. Wilentz, P. Argani, T. A. Sohn, C. J. Yeo, J. L. Cameron, S. E. Kern, and R. H. Hruban Dpc-4 Protein Is Expressed in Virtually All Human Intraductal Papillary Mucinous Neoplasms of the Pancreas : Comparison with Conventional Ductal Adenocarcinomas Am. J. Pathol., September 1, 2000; 157(3): 755 - 761. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. Hruban, R. E. Wilentz, and S. E. Kern Genetic Progression in the Pancreatic Ducts Am. J. Pathol., June 1, 2000; 156(6): 1821 - 1825. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Wilentz, C. A. Iacobuzio-Donahue, P. Argani, D. M. McCarthy, J. L. Parsons, C. J. Yeo, S. E. Kern, and R. H. Hruban Loss of Expression of Dpc4 in Pancreatic Intraepithelial Neoplasia: Evidence That DPC4 Inactivation Occurs Late in Neoplastic Progression Cancer Res., April 1, 2000; 60(7): 2002 - 2006. [Abstract] [Full Text]
|
|
|
|
|
|
K. L. Woodford-Richens, A. J. Rowan, P. Gorman, S. Halford, D. C. Bicknell, H. S. Wasan, R. R. Roylance, W. F. Bodmer, and I. P. M. Tomlinson SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway PNAS, August 14, 2001; 98(17): 9719 - 9723. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
