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 germline mutations in familial gastric cancer

Abstract

The identification of genes predisposing to familial cancer is an essential step towards understanding the molecular events underlying tumorigenesis and is critical for the clinical management of affected families. Despite a declining incidence, gastric cancer remains a major cause of cancer death worldwide1, and about 10% of cases show familial clustering2,3. The relative contributions of inherited susceptibility and environmental effects to familial gastric cancer are poorly understood because little is known of the genetic events that predispose to gastric cancer. Here we describe the identification of the gene responsible for early-onset, histologically poorly differentiated, high grade, diffuse gastric cancer4 in a large kindred from New Zealand (Aotearoa). Genetic linkage analysis demonstrated significant linkage to markers flanking the gene for the calcium-dependent cell–adhesion protein E-cadherin. Sequencing of the E-cadherin gene revealed a G→ T nucleotide substitution in the donor splice consensus sequence of exon 7, leading to a truncated gene product. Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas5. Underexpression of E-cadherin is a prognostic marker of poor clinical outcome in many tumour types6, and restored expression of E-cadherin in tumour models can suppress the invasiveness of epithelial tumour cells7,8. The role of E-cadherin in gastric cancer susceptibility was confirmed by identifying inactivating mutations in other gastric cancer families. In one family, a frameshift mutation was identified in exon 15, and in a second family a premature stop codon interrupted exon 13. These results describe, to our knowledge for the first time, a molecular basis for familial gastric cancer, and confirm the important role of E-cadherin mutations in cancer.

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: Gastric cancer kindred (family A).
Figure 2: Identification of the mutation in family A.
Figure 3: Mutations in families B and C.

Similar content being viewed by others

References

  1. Howson, C. P., Hiyama, T. & Wynder, E. L. The decline in gastric cancer: Epidemiology of an unplanned triumph. Epidemiol. Rev. 8, 1–27 (1986).

    Article  CAS  PubMed  Google Scholar 

  2. La Vecchia, C., Negri, E., Franceschi, S. & Gentile, A. Family history and the risk of stomach and colorectal cancer. Cancer 70, 50–55 (1992).

    Article  CAS  PubMed  Google Scholar 

  3. Zanghieri, G. et al. Familial occurrence of gastric cancer in the 2-year experience of a population-based registry. Cancer 66, 2047–2051 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Lauren, P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol. Microbiol. Scand. 64, 31–49 (1965).

    Article  CAS  PubMed  Google Scholar 

  5. Shiozaki, H., Oka, H., Inoue, M., Tamura, S. & Monden, M. E-cadherin mediated adhesion system in cancer cells. Cancer 77, 1605–1613 (1995).

    Article  Google Scholar 

  6. Bracke, M. E., Roy, F. M. & Mareel, M. M. The E-cadherin/catenin complex in invasion and metastasis. Curr. Topics Microbiol. Imm. 213, 123–161 (1996).

    CAS  Google Scholar 

  7. Frixen, E. H. et al. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carinoma cells. J. Cell Biol. 113, 173–185 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. Vleminckx, K., Vakaet, L., Mareel, M., Fiers, W. & Roy, F. V. Genetic manipulation of E-cadherin expression by epithelial tumour cells reveals an invasion suppressor role. Cell 66, 107–119 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Jones, E. G. Familial gastric cancer. NZ Med. J. 63, 287–296 (1964).

    CAS  Google Scholar 

  10. Grunwald, G. B. The structural and functional analysis of cadherin calcium-dependent cell adhesion molecules. Curr. Opin. Cell Biol. 5, 797–805 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. GDB (TM) Human Genome Database. ( John Hopkins University, Baltimor, Maryland ).

  12. Dib, C. et al. Acomprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Berx, G. et al. E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J. 14, 6107–6115 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Padgett, R. A., Grabowski, P. J., Konarska, M. M., Seiler, S. & Sharp, P. A. Splicing of messenger RNA precursors. Annu. Rev. Biochem. 55, 1119–1150 (1986).

    Article  CAS  PubMed  Google Scholar 

  15. Weil, D. et al. The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Nature Genet. 16, 191–193 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Oda, T. et al. E-cadherin gene mutations in human gastric carcinoma cell lines. Proc. Natl Acad. Sci. USA 91, 1858–1862 (1994).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. Berx, G. et al. Cloning and characterization of the human invasion supressor gene E-cadherin (CDH1). Genomics 26, 281–289 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Nagar, B., Overduin, M., Ikura, M. & Rini, J. M. Structural basis of calcium-induced E-cadherin rigidification and imerization. Nature 380, 360–364 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Mahoney, P. A. et al. The fat tumour suppressor gene in Drosophila encodes a novel member of the cadherin gene superfamily. Cell 67, 853–868 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Becker, K.-F. et al. E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res. 54, 3845–3852 (1994).

    CAS  PubMed  Google Scholar 

  21. Muta, H. et al. E-cadherin mutations in signet ring cell carcinoma of the stomach. Jap. J. Cancer Res. 87, 843–848 (1996).

    Article  CAS  Google Scholar 

  22. Tamura, G. et al. Inactivation of the E-cadherin gene in primary gastric carcinomas and gastric carcinoma cell lines. Jap. J. Cancer Res. 87, 1153–1159 (1996).

    Article  CAS  Google Scholar 

  23. Berx, G. et al. E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 13, 1919–1925 (1996).

    CAS  PubMed  Google Scholar 

  24. Risinger, J. I., Berchuck, A., Kohler, M. F. & Boyd, J. Mutations of the E-cadherin gene in human gynaecologic cancers. Nature Genet. 7, 98–102 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Yoshiura, K. et al. Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc. Natl Acad. Sci. USA 92, 7416–7419 (1995).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Graff, J. R. et al. E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res. 55, 5195–5199 (1995).

    CAS  PubMed  Google Scholar 

  27. Morin, P. J. et al. Activation of β catenin-Tcf signalling in colon cancer mutations in β catenin or APC. Science 275, 1787–1792 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Banerjee, S. K., Makdisi, W. F., Weston, A. P., Mitchell, S. M. & Campbell, D. R. Microwave-based DNA extraction from paraffin-embedded tissue for PCR amplification. Biotechniques 18, 768–773 (1995).

    CAS  PubMed  Google Scholar 

  29. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analyt. Biochem. 162, 156–159 (1987).

    Article  CAS  PubMed  Google Scholar 

  30. Lathrop, G. M., Lalouel, J. M., Julier, C. & Ott, J. Multilocus linkage analysis in humans: Detection of linkage and estimation of recombination. Am. J. Hum. Genet. 37, 482–498 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge the support of the New Zealand Lottery Grants Board, Health Research Council of New Zealand, Maurice and Phyllis Paykel Trust, Healthcare Otago Charitable Trust and the Cancer Society of New Zealand; we thank G. Barbezat, J. Cutfield, R. J. M. Gardner, D. Perez, T.Sutton, E. Richardson, D. Shaw, L. Scanlon, J. Ratema, J. Dunphy, I. Morison, M. Eccles for advice and the participating families.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Parry Guilford.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guilford, P., Hopkins, J., Harraway, J. et al. E-cadherin germline mutations in familial gastric cancer. Nature 392, 402–405 (1998). https://doi.org/10.1038/32918

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/32918

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing