Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma

Abstract

In diffuse gastric carcinoma, despite common E-cadherin gene (CDH1) mutations, tumors show absence of CDH1 loss of heterozigosity (LOH) in most cases. This observation challenges the classical two-hit model of tumor suppressor gene inactivation. In order to investigate whether or not CDH1 promoter methylation may function as the second hit we analysed a series of 23 sporadic gastric carcinomas for the presence of CDH1 mutations, CDH1 promoter methylation, LOH and E-cadherin expression. CDH1 mutations were detected in nine of the 16 (56.3%) diffuse gastric carcinomas and in none of the seven intestinal gastric carcinomas. In diffuse gastric carcinomas harboring CDH1 mutations, LOH was observed in a single case. Loss of plasma membrane E-cadherin expression was consistently found in all nine cases with CDH1 mutation, suggesting that tumors inactivated the remaining CDH1 allele via a different mechanism. CDH1 promoter methylation was observed in nine of the 16 (56.3%) diffuse-type gastric carcinoma cases, including six of the nine cases (66.7%) harboring CDH1 mutations. CDH1 promoter methylation was also seen in two (28.6%) intestinal-type cases. Our results show that CDH1 promoter methylation is the second hit in more than half of the sporadic diffuse gastric carcinoma cases harboring CDH1 mutations.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  • Becker KF, Atkinson MJ, Reich U, Becker I, Nekarda H, Siewert JR, Hofler H . 1994 Cancer Res. 54: 3845–3852

  • Berx G, Becker KF, Hofler H, van Roy F . 1998 Hum. Mutat. 12: 226–237

  • Berx G, Cleton-Jansen AM, Nollet F, de Leeuw WJ, van de Vijver M, Cornelisse C, van Roy F . 1995 EMBO J. 14: 6107–6115

  • Berx G, Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F, Cornelisse C . 1996 Oncogene 13: 1919–1925

  • Gayther SA, Gorringe KL, Ramus SJ, Huntsman D, Roviello F, Grehan N, Machado JC, Pinto E, Seruca R, Halling K, MacLeod P, Powell SM, Jackson CE, Ponder BAJ, Caldas C . 1998 Cancer Res. 58: 4086–4089

  • Grady WM, Willis J, Guilford PJ, Dunbier AK, Toro TT, Lynch H, Wiesner G, Ferguson K, Eng C, Park JG, Kim SJ, Markowitz S . 2000 Nat. Genet. 26: 16–17

  • Graff JR, Gabrielson E, Fujii H, Baylin SB, Herman JG . 2000 J. Biol. Chem. 275: 2727–2732

  • Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE, Baylin SB . 1995 Cancer Res. 55: 5195–5199

  • Graff JR, Herman JG, Myohanen S, Baylin SB, Vertino PM . 1997 J. Biol. Chem. 272: 22322–22329

  • Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE . 1998 Nature 392: 402–405

  • Handschuh G, Candidus S, Luber B, Reich U, Schott C, Oswald S, Becke H, Hutzler P, Birchmeier W, Hofler H, Becker KF . 1999 Oncogene 18: 4301–4312

  • Hennig G, Behrens J, Truss M, Frisch S, Reichmann E, Birchmeier W . 1995 Oncogene 11: 475–484

  • Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . 1996 Proc. Natl. Acad. Sci. USA 93: 9821–9826

  • Iida S, Akiyama Y, Nakajima T, Ichikawa W, Nihei Z, Sugihara K, Uasa Y . 2000 Int. J. Cancer 87: 654–658

  • Kang SH, Bang YJ, Im YH, Yang HK, Lee DA, Lee HY, Lee HS, Kim NK, Kim SJ . 1999 Oncogene 18: 7280–7286

  • Lee YY, Kang SH, Seo JY, Jung CW, Lee KU, Choe KJ, Kim BK, Kim NK, Koeffler HP, Bang YJ . 1997 Cancer 80: 1889–1896

  • Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS, Ho JC . 1999 Cancer Res. 59: 159–164

  • Luber B, Candidus S, Handschuh G, Mentele E, Hutzler P, Feller S, Voss J, Hofler H, Becker KF . 2000 Cell Adhes. Commun. 7: 391–408

  • Machado JC, Carneiro F, Beck S, Rossi S, Lopes J, Taveira-Gomes A, Cardoso-Oliveira M . 1998 Int. J. Surg. Pathol. 6: 135–144

  • Machado JC, Soares P, Carneiro F, Rocha A, Beck S, Blin N, Berx G, Sobrinho-Simöes M . 1999 Lab. Invest. 79: 459–465

  • Shin JY, Kim HS, Park J, Park JB, Lee JY . 2000 Cancer Res. 60: 262–265

  • Takeichi M . 1991 Science 251: 1451–1455

  • Tamura G, Yin J, Wang S, Fleisher AS, Zou T, Abraham JM, Kong D, Smolinski KN, Wilson KT, James SP, Silverberg SG, Nishizuka S, Tershima M, Motoyama T, Meltzer SJ . 2000 J. Natl. Cancer Inst. 92: 569–573

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Machado, J., Oliveira, C., Carvalho, R. et al. E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma. Oncogene 20, 1525–1528 (2001). https://doi.org/10.1038/sj.onc.1204234

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204234

Keywords

This article is cited by

Search

Quick links