Abstract
Truncating mutations in the gene for the cell to cell adhesion protein E-cadherin are the most consistent genetic alterations observed in sporadic and hereditary diffuse gastric cancer (DGC). In addition to these inactivating mutations, a CDH1 promoter polymorphism at position −160 has been reported to lead to transcriptional downregulation of the gene in vitro. We therefore performed a case–control study to investigate whether this variant is associated with an increased susceptibility to DGC. The frequency of the −160A allele was significantly higher (P<0.005) in 53 diffuse gastric cancer cases compared to 70 matched controls. The odds ratio associated with the A-allele was 2.27 for CA-heterozygotes (95%CI 1.16–4.44) and 7.84 for AA-homozygotes (95%CI 2.89–21.24). Two additional polymorphisms (the 48+6T→C and the 2076C→T variant) were genotyped and shown to be equally distributed among cases and controls. Haplotype analysis with the three polymorphisms confirmed an association with disease (P<0.004). However, this analysis suggested the −160C→A CDH1 promoter polymorphism may be in linkage disequilibrium with a distinct aetiological locus or acts in combination with other functional variants in or near the CDH1 region.
Similar content being viewed by others
References
Avizienyte E, Launonen V, Salovaara R, Kiviluoto T, Aaltonen LA . 2001 J. Med. Genet. 38: 49–52
Berx G, Becker KF, Hofler H, van Roy F . 1998 Hum. Mutat. 12: 226–237
Borch K, Jonsson B, Tarpila E, Franzen T, Berglund J, Kullman E, Franzen L . 2000 Br. J. Surg. 87: 618–626
Dempster AP, Laird NM, Rubin DB . 1977 J. R. Stat. Soc. B 39: 1–38
Devlin B, Risch N . 1995 Genomics 29: 311–322
Dunbier A, Guilford P . 2001 Adv. Cancer Res. 83: 55–65
Fisher RA (ed). . 1951 The design of experiments London: Oliver and Boyd Ltd pp. 1–244
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
Howson CP, Hiyama T, Wynder EL . 1986 Epidemiol. Rev. 8: 1–27
Humar B, Toro TT, Graziano F, Muller H, Dobbie Z, Kwang-Yan H, Eng C, Hampel H, Gilbert D, Winship I, Parry S, Ward R, Findlay MP, Christian A, Tucker M, Tucker K, Merriman T, Guilford P . 2002 Hum. Mutat. 19: 518–525
Koeleman BP, Dudbridge F, Cordell HJ, Todd JA . 2000 Ann. Hum. Genet. 64: 207–213
Lauren P . 1965 Acta Pathol. Microbiol. Scand. 64: 31–49
Lauren PA, Nevalainen TJ . 1993 Cancer 71: 2926–2933
Lei H, Sjoberg-Margolin S, Salahshor S, Werelius B, Jandakova E, Hemminki K, Lindblom A, Vorechovsky I . 2002 Int. J. Cancer 98: 199–204
Li LC, Chui RM, Sasaki M, Nakajima K, Perinchery G, Au HC, Nojima D, Carroll P, Dahiya R . 2000 Cancer Res. 60: 873–876
Porter TR, Richards FM, Houlston RS, Evans DG, Jankowski JA, MacDonald F, Norbury G, Payne SJ, Fisher SA, Tomlinson I, Maher ER . 2002 Oncogene 21: 1928–1933
Risinger JI, Berchuck A, Kohler MF, Boyd J . 1994 Nat. Genet. 7: 98–102
Spielman RS, McGinnis RE, Ewens WJ . 1993 Am. J. Hum. Genet. 52: 506–516
Wu MS, Huang SP, Chang YT, Lin MT, Shun CT, Chang MC, Wang HP, Chen CJ, Lin JT . 2002 Cancer 94: 1443–1448
Acknowledgements
We thank all the patients and volunteers who contributed to this study. We also thank Natalie J Kerr and Anita Dunbier for critical reading of the manuscript. B Humar was supported by a grant from the Swiss Cancer League (BIL SKL 993-02-2000) and the Swiss National Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Humar, B., Graziano, F., Cascinu, S. et al. Association of CDH1 haplotypes with susceptibility to sporadic diffuse gastric cancer. Oncogene 21, 8192–8195 (2002). https://doi.org/10.1038/sj.onc.1205921
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205921
- Springer Nature Limited
Keywords
This article is cited by
-
The transcriptional regulator FUBP1 influences disease outcome in murine and human myeloid leukemia
Leukemia (2019)
-
Lack of association between the CDH1 polymorphism and gastric cancer susceptibility: a meta-analysis
Scientific Reports (2015)
-
CDH1 polymorphisms and haplotypes in sporadic diffuse and intestinal gastric cancer: a case–control study based on direct sequencing analysis
World Journal of Surgical Oncology (2014)
-
Helicobacter pylori CagA promotes Snail-mediated epithelial–mesenchymal transition by reducing GSK-3 activity
Nature Communications (2014)
-
Prophylactic total gastrectomy in hereditary diffuse gastric cancer: identification of two novel CDH1 gene mutations—a clinical observational study
Familial Cancer (2014)