This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Powell, S. M. Articles by Cummings, O. W. Search for Related Content PubMed PubMed Citation Articles by Powell, S. M. Articles by Cummings, O. W.

Inactivation of Smad4 in Gastric Carcinomas¹

Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22906-0013 [S. M. P., J. C. H.]; Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196 [S. R. H., C. R. R.]; and Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana 46202 [O. W. C.]

Allelic loss of chromosome 18q has been noted in intestinal type gastric adenocarcinomas. Smad4 is a gene located at 18q that was recently cloned in humans and found to be significantly altered in pancreatic cancers. We sought to determine whether Smad4 genetic alterations played a significant role in gastric tumorigenesis by studying 35 gastric adenocarcinomas of all histopathological types and pathological stages. Microdissected specimens were used for mutational analysis of Smad4 at the nucleotide level, including the entire coding region and intron/exon boundaries. Allelic imbalance was also analyzed at the Smad4 locus using two nearby microsatellite markers.

One case of apparent biallelic inactivation of Smad4 was found in our study of 35 gastric carcinomas. A nonsense point mutation at codon 334 was demonstrated, which, similar to other Smad4 mutations, is predicted to truncate the conserved COOH-terminal domain of this protein. This Smad4 C to T transition mutation was proven to be somatically acquired. Allelic loss was also noted on chromosome 18q at a marker near Smad4 in this mutated gastric cancer, apparently producing complete inactivation of Smad4 in this tumor. Significant 18q allelic loss (56% of 34 informative cases) was noted in our gastric carcinomas using microsatellite markers near the Smad4 locus, regardless of histological subtype or pathological stage. Additionally, three cases of microsatellite instability were observed.

Thus, Smad4 inactivation was noted in our gastric carcinomas; however, this event was rare. The frequent loss of chromosomal arm 18q observed in gastric cancers suggests the presence of other tumor suppressor genes in this region that are involved in gastric tumorigenesis. Further studies are needed to identify these other targets of inactivation during gastric cancer development.

¹ This work was supported in part by NIH Grant 1R29CA6790001 and a Foundation American Gastrointestinal Association Research Scholarship award.

² To whom requests for reprints should be addressed, at University of Virginia Health Sciences Center, Box 10013, Charlottesville, VA 22906-0013.

Received 7/16/97. Accepted 8/15/97.

This article has been cited by other articles:

				L.-H. Wang, S.-H. Kim, J. H. Lee, Y.-L. Choi, Y. C. Kim, T. S. Park, Y.-C. Hong, C.-F. Wu, and Y. K. Shin Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression Clin. Cancer Res., January 1, 2007; 13(1): 102 - 110. [Abstract] [Full Text] [PDF]

				H. Okano, H. Shinohara, A. Miyamoto, K. Takaori, and N. Tanigawa Concomitant Overexpression of Cyclooxygenase-2 in HER-2-Positive on Smad4-Reduced Human Gastric Carcinomas Is Associated with a Poor Patient Outcome Clin. Cancer Res., October 15, 2004; 10(20): 6938 - 6945. [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]

				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]

				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]

				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]

				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]

				W. A. Gramley, A. Asghar, H. F. Frierson Jr., and S. M. Powell Detection of Helicobacter pylori DNA in Fecal Samples from Infected Individuals J. Clin. Microbiol., July 1, 1999; 37(7): 2236 - 2240. [Abstract] [Full Text]

				K. C. Halling, J. Harper, C. A. Moskaluk, S. N. Thibodeau, G. R. Petroni, A. S. Yustein, P. Tosi, C. Minacci, F. Roviello, P. Piva, et al. Origin of Microsatellite Instability in Gastric Cancer Am. J. Pathol., July 1, 1999; 155(1): 205 - 211. [Abstract] [Full Text] [PDF]

				A. S. Yustein, J. C. Harper, G. R. Petroni, O. W. Cummings, C. A. Moskaluk, and S. M. Powell Allelotype of Gastric Adenocarcinoma Cancer Res., April 1, 1999; 59(7): 1437 - 1441. [Abstract] [Full Text] [PDF]

				D. Saha, P. K. Datta, and R. D. Beauchamp Oncogenic Ras Represses Transforming Growth Factor-beta /Smad Signaling by Degrading Tumor Suppressor Smad4 J. Biol. Chem., July 27, 2001; 276(31): 29531 - 29537. [Abstract] [Full Text] [PDF]