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[Cancer Research 56, 2527-2530, June 1, 1996]
© 1996 American Association for Cancer Research
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DPC4 Gene in Various Tumor Types1

Mieke Schutte, Ralph H. Hruban, Lora Hedrick, Kathleen R. Cho, Gyongyi Molnar Nadasdy, Craig L. Weinstein, G. Steven Bova, William B. Isaacs, Paul Cairns, Homaira Nawroz, David Sidransky, Robert A. Casero, Jr., Paul S. Meltzer, Stephan A. Hahn and Scott E. Kern2

Departments of Pathology [M. S., R. H. H., L. H., K. R. C., G. M. N., C. W., G. S. B., S. A. H., S. E. K.], Oncology [R. H. H., G. S. B., W. B. I., D. S. R. A. C., S. E. K.], Urology [G. S. B., W. B. I.], and Otolaryngology [P. C., H. N., D. S.], The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, and Laboratory of Cancer Genetics, National Center of Human Genome Research, National Institutes of Health, Bethesda, Maryland 20892 [P. S. M.]

We recently identified a novel tumor-suppressor gene, DPC4, at chromosome 18q21.1 and found that both alleles of DPC4 were inactivated in nearly one-half of the pancreatic carcinomas. Here, we analyzed 338 tumors, originating from 12 distinct anatomic sites, for alterations in the DPC4 gene. Sixty-four specimens were selected for the presence of the allelic loss of 18q and were further analyzed for DPC4 sequence alterations. An alteration of the DPC4 gene sequence was identified in one of eight breast carcinomas and one of eight ovarian carcinomas. These results indicate that whereas DPC4 inactivation is prevalent in pancreatic carcinoma (48%), it is distinctly uncommon (<10%) in the other tumor types examined. The tissue restriction of alterations in DPC4, as in many other tumor-suppressor genes, emphasizes the complexity of rate-limiting checkpoints in human tumorigenesis.

1 This work was supported by the SPORE (Specialized Program of Research Excellence) for Gastrointestinal Cancer, NIH Grant CA62924. S. E. K. is a McDonnell Foundation Scholar.

2 To whom requests for reprints should be addressed, at Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21205-2196. Phone: (410) 614-3314; Fax: 614-0671.

Received 4/ 5/96. Accepted 4/15/96.




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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]

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 Proc. Natl. Acad. Sci. USAHome page
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]

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 Genes Dev.Home page
D. K. Lee, S. H. Park, Y. Yi, S.-G. Choi, C. Lee, W. T. Parks, H. Cho, M. P. de Caestecker, Y. Shaul, A. B. Roberts, et al.
The hepatitis B virus encoded oncoprotein pX amplifies TGF-{beta} family signaling through direct interaction with Smad4: potential mechanism of hepatitis B virus-induced liver fibrosis
Genes & Dev., February 15, 2001; 15(4): 455 - 466.
[Abstract] [Full Text]

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 Cell Growth Differ.Home page
S. W. Tobin, M. K. Brown, K. Douville, D. C. Payne, A. Eastman, and B. A. Arrick
Inhibition of Transforming Growth Factor {beta} Signaling in MCF-7 Cells Results in Resistance to Tumor Necrosis Factor {{alpha}}: A Role for Bcl-2
Cell Growth Differ., February 1, 2001; 12(2): 109 - 117.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
C. Xiangming, S. Natsugoe, S. Takao, S. Hokita, S. Ishigami, G. Tanabe, M. Baba, K. Kuroshima, and T. Aikou
Preserved Smad4 Expression in the Transforming Growth Factor {beta} Signaling Pathway Is a Favorable Prognostic Factor in Patients with Advanced Gastric Cancer
Clin. Cancer Res., February 1, 2001; 7(2): 277 - 282.
[Abstract] [Full Text]

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 Am. J. Pathol.Home page
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]

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 Proc. Natl. Acad. Sci. USAHome page
C.-R. Chen, Y. Kang, and J. Massague
Inaugural Article: Defective repression of c-myc in breast cancer cells: A loss at the core of the transforming growth factor beta growth arrest program
PNAS, January 30, 2001; 98(3): 992 - 999.
[Abstract] [Full Text] [PDF]

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 Cell Growth Differ.Home page
S. H. Park, M. C. Birchenall-Roberts, Y. Yi, B. I. Lee, D. K. Lee, D. C. Bertolette, T. Fu, F. Ruscetti, and S.-J. Kim
Mechanism of Induction of Transforming Growth Factor-{beta} Type II Receptor Gene Expression by v-Src in Murine Myeloid Cells
Cell Growth Differ., January 1, 2001; 12(1): 9 - 18.
[Abstract] [Full Text]

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 Cancer Res.Home page
S. P. Fink, S. E. Swinler, J. D. Lutterbaugh, J. Massagué, S. Thiagalingam, K. W. Kinzler, B. Vogelstein, J. K. V. Willson, and S. Markowitz
Transforming Growth Factor-{beta}-induced Growth Inhibition in a Smad4 Mutant Colon Adenoma Cell Line
Cancer Res., January 1, 2001; 61(1): 256 - 260.
[Abstract] [Full Text]

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 Mol. Cell. Biol.Home page
C. E. Pierreux, F. J. Nicolás, and C. S. Hill
Transforming Growth Factor beta -Independent Shuttling of Smad4 between the Cytoplasm and Nucleus
Mol. Cell. Biol., December 1, 2000; 20(23): 9041 - 9054.
[Abstract] [Full Text]

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 Am. J. Physiol. Cell Physiol.Home page
J. N. Rao, L. Li, B. L. Bass, and J.-Y. Wang
Expression of the TGF-beta receptor gene and sensitivity to growth inhibition following polyamine depletion
Am J Physiol Cell Physiol, October 1, 2000; 279(4): C1034 - C1044.
[Abstract] [Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
M. P. de Caestecker, E. Piek, and A. B. Roberts
Role of Transforming Growth Factor-{beta} Signaling in Cancer
J Natl Cancer Inst, September 6, 2000; 92(17): 1388 - 1402.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
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]

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 Proc. Natl. Acad. Sci. USAHome page
I. Schwarte-Waldhoff, O. V. Volpert, N. P. Bouck, B. Sipos, S. A. Hahn, S. Klein-Scory, J. Luttges, G. Kloppel, U. Graeven, C. Eilert-Micus, et al.
Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis
PNAS, August 15, 2000; 97(17): 9624 - 9629.
[Abstract] [Full Text] [PDF]

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 Nucleic Acids ResHome page
J. B. Jones and S. E. Kern
Functional mapping of the MH1 DNA-binding domain of DPC4/SMAD4
Nucleic Acids Res., June 15, 2000; 28(12): 2363 - 2368.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
M. Yamano, H. Fujii, T. Takagaki, N. Kadowaki, H. Watanabe, and T. Shirai
Genetic Progression and Divergence in Pancreatic Carcinoma
Am. J. Pathol., June 1, 2000; 156(6): 2123 - 2133.
[Abstract] [Full Text] [PDF]

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 GutHome page
K Woodford-Richens, S Bevan, M Churchman, B Dowling, D Jones, C G Norbury, S V Hodgson, D Desai, K Neale, R K S Phillips, et al.
Analysis of genetic and phenotypic heterogeneity in juvenile polyposis
Gut, May 1, 2000; 46(5): 656 - 660.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
J. Xu and L. Attisano
Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor beta signaling by targeting Smads to the ubiquitin-proteasome pathway
PNAS, April 25, 2000; 97(9): 4820 - 4825.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
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]

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 Cancer Res.Home page
K. Matsuzaki, M. Date, F. Furukawa, Y. Tahashi, M. Matsushita, K. Sakitani, N. Yamashiki, T. Seki, H. Saito, M. Nishizawa, et al.
Autocrine Stimulatory Mechanism by Transforming Growth Factor {beta} in Human Hepatocellular Carcinoma
Cancer Res., March 1, 2000; 60(5): 1394 - 1402.
[Abstract] [Full Text]

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 Cancer Res.Home page
M. Bouras, E. Tabone, J. Bertholon, P. Sommer, R. Bouvier, J.-P. Droz, and M. Benahmed
A Novel SMAD4 Gene Mutation in Seminoma Germ Cell Tumors
Cancer Res., February 1, 2000; 60(4): 922 - 928.
[Abstract] [Full Text]

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 Proc. Natl. Acad. Sci. USAHome page
M. Tan, Y. Wang, K. Guan, and Y. Sun
PTGF-beta , a type beta transforming growth factor (TGF-beta ) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-beta signaling pathway
PNAS, January 4, 2000; 97(1): 109 - 114.
[Abstract] [Full Text] [PDF]

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 J. Cell Sci.Home page
J. MacDougall and L. Matrisian
Targets of extinction: identification of genes whose expression is repressed as a consequence of somatic fusion between cells representing basal and luminal mammary epithelial phenotypes
J. Cell Sci., January 2, 2000; 113(3): 409 - 423.
[Abstract] [PDF]

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 Cell Growth Differ.Home page
S. Larisch-Bloch, D. Danielpour, N. S. Roche, R. Lotan, A. Y. Hsing, H. Kerner, T. Hajouj, R. J. Lechleider, and A. B. Roberts
Selective Loss of the Transforming Growth Factor-{beta} Apoptotic Signaling Pathway in Mutant NRP-154 Rat Prostatic Epithelial Cells
Cell Growth Differ., January 1, 2000; 11(1): 1 - 10.
[Abstract] [Full Text]

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 Am. J. Pathol.Home page
R. E. Wilentz, G. H. Su, J. L. Dai, A. B. Sparks, P. Argani, T. A. Sohn, C. J. Yeo, S. E. Kern, and R. H. Hruban
Immunohistochemical Labeling for Dpc4 Mirrors Genetic Status in Pancreatic Adenocarcinomas : A New Marker of DPC4 Inactivation
Am. J. Pathol., January 1, 2000; 156(1): 37 - 43.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
M. E. Engel, M. A. McDonnell, B. K. Law, and H. L. Moses
Interdependent SMAD and JNK Signaling in Transforming Growth Factor-beta -mediated Transcription
J. Biol. Chem., December 24, 1999; 274(52): 37413 - 37420.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
E. PIEK, C.-H. HELDIN, and P. TEN DIJKE
Specificity, diversity, and regulation in TGF-{beta} superfamily signaling
FASEB J, December 1, 1999; 13(15): 2105 - 2124.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
M. J. Calonge and J. Massague
Smad4/DPC4 Silencing and Hyperactive Ras Jointly Disrupt Transforming Growth Factor-beta Antiproliferative Responses in Colon Cancer Cells
J. Biol. Chem., November 19, 1999; 274(47): 33637 - 33643.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
B. Pasche, P. Kolachana, K. Nafa, J. Satagopan, Y.-G. Chen, R. S. Lo, D. Brener, D. Yang, L. Kirstein, C. Oddoux, et al.
T{{beta}}R-I(6A) Is a Candidate Tumor Susceptibility Allele
Cancer Res., November 1, 1999; 59(22): 5678 - 5682.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
W. Bruening, A. H. Prowse, D. C. Schultz, M. Holgado-Madruga, A. Wong, and A. K. Godwin
Expression of OVCA1, a Candidate Tumor Suppressor, Is Reduced in Tumors and Inhibits Growth of Ovarian Cancer Cells
Cancer Res., October 1, 1999; 59(19): 4973 - 4983.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
S. Knuutila, Y. Aalto, K. Autio, A.-M. Bjorkqvist, W.'e. El-Rifai, S. Hemmer, T. Huhta, E. Kettunen, S. Kiuru-Kuhlefelt, M. L. Larramendy, et al.
DNA Copy Number Losses in Human Neoplasms
Am. J. Pathol., September 1, 1999; 155(3): 683 - 694.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
R. Anbazhagan, D. M. Bornman, J. C. Johnston, W. H. Westra, and E. Gabrielson
The S387Y Mutation of the Transforming Growth Factor-{beta} Receptor Type I Gene Is Uncommon in Metastases of Breast Cancer and Other Common Types of Adenocarcinoma
Cancer Res., July 1, 1999; 59(14): 3363 - 3364.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. L. Stroschein, W. Wang, and K. Luo
Cooperative Binding of Smad Proteins to Two Adjacent DNA Elements in the Plasminogen Activator Inhibitor-1 Promoter Mediates Transforming Growth Factor beta -induced Smad-dependent Transcriptional Activation
J. Biol. Chem., April 2, 1999; 274(14): 9431 - 9441.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
M. B. Datto, J. P. Frederick, L. Pan, A. J. Borton, Y. Zhuang, and X.-F. Wang
Targeted Disruption of Smad3 Reveals an Essential Role in Transforming Growth Factor beta -Mediated Signal Transduction
Mol. Cell. Biol., April 1, 1999; 19(4): 2495 - 2504.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
J. L. Dai, R. K. Bansal, and S. E. Kern
G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: Phenotypes reversed by a tumorigenic mutation
PNAS, February 16, 1999; 96(4): 1427 - 1432.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
U. Rodeck, T. Nishiyama, and A. Mauviel
Independent Regulation of Growth and SMAD-mediated Transcription by Transforming Growth Factor {beta} in Human Melanoma Cells
Cancer Res., February 1, 1999; 59(3): 547 - 550.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
W. M. Grady, L. L. Myeroff, S. E. Swinler, A. Rajput, S. Thiagalingam, J. D. Lutterbaugh, A. Neumann, M. G. Brattain, J. Chang, S.-J. Kim, et al.
Mutational Inactivation of Transforming Growth Factor {beta} Receptor Type II in Microsatellite Stable Colon Cancers
Cancer Res., January 1, 1999; 59(2): 320 - 324.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
N. Suh, Y. Wang, T. Honda, G. W. Gribble, E. Dmitrovsky, W. F. Hickey, R. A. Maue, A. E. Place, D. M. Porter, M. J. Spinella, et al.
A Novel Synthetic Oleanane Triterpenoid, 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid, with Potent Differentiating, Antiproliferative, and Anti-Inflammatory Activity
Cancer Res., January 1, 1999; 59(2): 336 - 341.
[Abstract] [Full Text] [PDF]

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 ScienceHome page
P. Sun, P. Dong, K. Dai, G. J. Hannon, and D. Beach
p53-Independent Role of MDM2 in TGF-1 Resistance
Science, December 18, 1998; 282(5397): 2270 - 2272.
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