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Genetic variants A1826H and D2937Y in GAG-β domain of versican influence susceptibility to intestinal-type gastric cancer

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Abstract

Purpose

Versican regulates adhesion, migration, proliferation, and survival of cells, and plays an important role in cancer development. A case–control association study was performed to test genetic association of versican polymorphisms with susceptibility to gastric cancer.

Methods

In this study, 1,101 unrelated Korean subjects including 612 gastric cancer patients and 489 healthy controls were genotyped for all 21 exonic polymorphisms in the versican gene (VCAN) encoding amino acid changes in versican. Cancer susceptibility associations with the polymorphisms were assessed using multivariate logistic regression analysis with adjustment for age and gender and with control for multiple testing.

Results

Two amino acid changes in GAG-β domain of versican encoded by two almost fully correlated (r 2 = 0.97) nonsynonymous single-nucleotide polymorphisms in VCAN were associated with gastric cancer. The association was evident in intestinal-type but not in diffuse-type gastric cancer. The minor-allele homozygote of rs188703 (G > A, R1826H) or rs160277 (G > T, D2937Y) was significantly associated with a twofold decreased susceptibility to intestinal-type gastric cancer when compared with the other genotypes (adjusted odds ratio = 0.52 or 0.51, P = 0.0098 or 0.0087, respectively).

Conclusions

The intestinal-type gastric cancer susceptibility is associated with two amino acid changes of versican in the GAG-β domain, which is critical for enhancement of cell proliferation and activation of EGFR signal pathway by versican, and changes from the major to minor alleles may impair the function to decrease susceptibility to cancer.

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Fig. 1

Abbreviations

CI:

Confidence interval

GAG:

Glycosaminoglycan

LD:

Linkage disequilibrium

OR:

Odds ratio

SNP:

Single-nucleotide polymorphism

References

  1. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

  2. Boussioutas A, Li H, Liu J, Waring P, Lade S, Holloway AJ, Taupin D, Gorringe K, Haviv I, Desmond PV, Bowtell DD (2003) Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer. Cancer Res 63:2569–2577

  3. Brown LF, Guidi AJ, Schnitt SJ, Van De Water L, Iruela-Arispe ML, Yeo TK, Tognazzi K, Dvorak HF (1999) Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin Cancer Res 5:1041–1056

  4. Cattaruzza S, Schiappacassi M, Kimata K, Colombatti A, Perris R (2004) The globular domains of PG-M/versican modulate the proliferation-apoptosis equilibrium and invasive capabilities of tumor cells. FASEB J 18:779–781

  5. Dours-Zimmermann MT, Zimmermann DR (1994) A novel glycosaminoglycan attachment domain identified in two alternative splice variants of human versican. J Biol Chem 269:32992–32998

  6. Evanko SP, Angello JC, Wight TN (1999) Formation of hyaluronan- and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 19:1004–1013

  7. Hippo Y, Taniguchi H, Tsutsumi S, Machida N, Chong JM, Fukayama M, Kodama T, Aburatani H (2002) Global gene expression analysis of gastric cancer by oligonucleotide microarrays. Cancer Res 62:233–240

  8. Kim SY, Kim JH, Lee HS, Noh SM, Song KS, Cho JS, Jeong HY, Kim WH, Yeom YI, Kim NS, Kim S, Yoo HS, Kim YS (2007) Meta- and gene set analysis of stomach cancer gene expression data. Mol Cells 24:200–209

  9. Landolt RM, Vaughan L, Winterhalter KH, Zimmermann DR (1995) Versican is selectively expressed in embryonic tissues that act as barriers to neural crest cell migration and axon outgrowth. Development 121:2303–2312

  10. LaPierre DP, Lee DY, Li SZ, Xie YZ, Zhong L, Sheng W, Deng Z, Yang BB (2007) The ability of versican to simultaneously cause apoptotic resistance and sensitivity. Cancer Res 67:4742–4750

  11. Lemire JM, Merrilees MJ, Braun KR, Wight TN (2002) Overexpression of the V3 variant of versican alters arterial smooth muscle cell adhesion, migration, and proliferation in vitro. J Cell Physiol 190:38–45

  12. Menashe I, Rosenberg PS, Chen BE (2008) PGA: power calculator for case-control genetic association analyses. BMC Genet 9:36

  13. Paulus W, Baur I, Dours-Zimmermann MT, Zimmermann DR (1996) Differential expression of versican isoforms in brain tumors. J Neuropathol Exp Neurol 55:528–533

  14. Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900

  15. Ricciardelli C, Brooks JH, Suwiwat S, Sakko AJ, Mayne K, Raymond WA, Seshadri R, LeBaron RG, Horsfall DJ (2002) Regulation of stromal versican expression by breast cancer cells and importance to relapse-free survival in patients with node-negative primary breast cancer. Clin Cancer Res 8:1054–1060

  16. Sakko AJ, Ricciardelli C, Mayne K, Tilley WD, Lebaron RG, Horsfall DJ (2001) Versican accumulation in human prostatic fibroblast cultures is enhanced by prostate cancer cell-derived transforming growth factor beta1. Cancer Res 61:926–930

  17. Schmalfeldt M, Dours-Zimmermann MT, Winterhalter KH, Zimmermann DR (1998) Versican V2 is a major extracellular matrix component of the mature bovine brain. J Biol Chem 273:15758–15764

  18. Serrano M, Massague J (2000) Networks of tumor suppressors. Workshop: tumor suppressor networks. EMBO Rep 1:115–119

  19. Sheng W, Wang G, Wang Y, Liang J, Wen J, Zheng PS, Wu Y, Lee V, Slingerland J, Dumont D, Yang BB (2005) The roles of versican V1 and V2 isoforms in cell proliferation and apoptosis. Mol Biol Cell 16:1330–1340

  20. Sheng W, Wang G, La Pierre DP, Wen J, Deng Z, Wong CK, Lee DY, Yang BB (2006) Versican mediates mesenchymal–epithelial transition. Mol Biol Cell 17:2009–2020

  21. Stephens M, Donnelly P (2003) A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:1162–1169

  22. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

  23. Theocharis AD (2008) Versican in health and disease. Connect Tissue Res 49:230–234

  24. Touab M, Villena J, Barranco C, Arumi-Uria M, Bassols A (2002) Versican is differentially expressed in human melanoma and may play a role in tumor development. Am J Pathol 160:549–557

  25. Wight TN (2002) Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr Opin Cell Biol 14:617–623

  26. Wight TN, Merrilees MJ (2004) Proteoglycans in atherosclerosis and restenosis: key roles for versican. Circ Res 94:1158–1167

  27. Wu Y, Wu J, Lee DY, Yee A, Cao L, Zhang Y, Kiani C, Yang BB (2005) Versican protects cells from oxidative stress-induced apoptosis. Matrix Biol 24:3–13

  28. Yang BL, Zhang Y, Cao L, Yang BB (1999) Cell adhesion and proliferation mediated through the G1 domain of versican. J Cell Biochem 72:210–220

  29. Yee AJ, Akens M, Yang BL, Finkelstein J, Zheng PS, Deng Z, Yang B (2007) The effect of versican G3 domain on local breast cancer invasiveness and bony metastasis. Breast Cancer Res 9:R47

  30. Zhang Y, Cao L, Yang BL, Yang BB (1998) The G3 domain of versican enhances cell proliferation via epidermial growth factor-like motifs. J Biol Chem 273:21342–21351

  31. Zheng PS, Wen J, Ang LC, Sheng W, Viloria-Petit A, Wang Y, Wu Y, Kerbel RS, Yang BB (2004) Versican/PG-M G3 domain promotes tumor growth and angiogenesis. FASEB J 18:754–756

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Acknowledgments

We appreciate Kyu-Sang Song for assistance in sample collection and Yikyeong Kim for technical and administrative assistance. This work was supported by grants from the Korea Healthcare Technology R&D Project [A084417]. H. Ju, B. Lim, M. Kim, and C. Kang are participants to the Brain Korea 21 Program. The sponsors had no role in design, performance or writing of the study.

Author information

Correspondence to Changwon Kang.

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Ju, H., Lim, B., Kim, M. et al. Genetic variants A1826H and D2937Y in GAG-β domain of versican influence susceptibility to intestinal-type gastric cancer. J Cancer Res Clin Oncol 136, 195 (2010). https://doi.org/10.1007/s00432-009-0647-8

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Keywords

  • CSPG2
  • Genetic association
  • Intestinal-type gastric cancer
  • SNP
  • Versican