J Korean Med Sci.  2008 Jun;23(3):421-427. 10.3346/jkms.2008.23.3.421.

Association of Vascular Endothelial Growth Factor Gene Polymorphisms with Susceptibility and Clinicopathologic Characteristics of Colorectal Cancer

• Chae YS
• Kim JG
• Sohn SK
• Cho YY
• Ahn BM
• Moon JH
• Jeon SW
• Park JY
• Lee IT
• Choi GS
• Jun SH

• KMID: 1786879
• DOI: http://doi.org/10.3346/jkms.2008.23.3.421

Abstract

Since vascular endothelial growth factor (VEGF) is known to be a potent pro-angiogenic factor, we evaluated the potential association of two VEGF gene polymorphisms (-634G>C and 936C>T) with the susceptibility and the clinicopathologic characteristics of colorectal cancer (CRC). The VEGF genotypes were determined using fresh colorectal tissue from 465 patients who had undergone a surgical resection and peripheral blood lymphocytes from 413 healthy controls by PCR/DHPLC assay. For the -634G>C polymorphism, the -634 GC or CC genotype was associated with a decreased risk of CRC (odds ratio [OR], 0.62; p=0.001) as a dominant model of C allele, whereas the 936 TT genotype correlated with advanced stage/ metastasis, a high serum level of CA19-9, and an higher grade in patients with CRC. In the haplotype analyses, haplotype -634C/936C and -634G/936T were associated with a decreased susceptibility of CRC (OR, 0.53 and 0.56; p<0.001, respectively). These observations imply that the VEGF gene polymorphisms may be associated with the susceptibility or clinicopathologic features of CRC. However, further studies of other VEGF sequence variants and their biological functions are needed to understand the role of the VEGF gene polymorphisms in the development and progression of CRC.

Keyword

Angiogenesis; Colorectal Neoplasms; Vascular Endothelial Growth Factors; Polymorphism, Genetic

MeSH Terms

Adult
Aged
Aged, 80 and over
Colorectal Neoplasms/*epidemiology/*genetics/secondary
Female
Genetic Predisposition to Disease/epidemiology
Haplotypes
Humans
Male
Middle Aged
Neovascularization, Pathologic/epidemiology/genetics/pathology
*Polymorphism, Genetic
Risk Factors
Vascular Endothelial Growth Factor A/*genetics

Figure

• 

  Fig. 1 Algorithm for genotyping of VEGF gene polymorphisms using a polymerase chain reaction/denaturing high-performance liquid chromatography (PCR/DHPLC) assay.

Reference

1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005. 55:74–108.

2. Pokorny RM, Hunt L, Galandiuk S. What's new with tumor markers for colorectal cancer? Dig Surg. 2000. 17:209–215.

3. Crawford NP, Colliver DW, Galandiuk S. Tumor markers and colorectal cancer: utility in management. J Surg Oncol. 2003. 84:239–248.

4. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature. 2000. 407:242–248.

5. Tran J, Master Z, Yu JL, Rak J, Dumont DJ, Kerbel RS. A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci USA. 2002. 99:4349–4354.

6. Bachelder RE, Crago A, Chung J, Wendt MA, Shaw LM, Robinson G, Mercurio AM. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res. 2001. 61:5736–5740.

7. Harmey JH, Bouchier-Hayes D. Vascular endothelial growth factor (VEGF), a survival factor for tumour cells: implications for antiangiogenic therapy. Bioessays. 2002. 24:280–283.

8. Katoh O, Takahashi T, Oguri T, Kuramoto K, Mihara K, Kobayashi M, Hirata S, Watanabe H. Vascular endothelial growth factor inhibits apoptotic death in hematopoietic cells after exposure to chemotherapeutic drugs by inducing MCL1 acting as an antiapoptotic factor. Cancer Res. 1998. 58:5565–5569.

9. Vincenti V, Cassano C, Rocchi M, Persico G. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation. 1996. 93:1493–1495.

10. Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE. Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine. 2000. 12:1232–1235.

11. Lin CC, Wu HC, Tsai FJ, Chen HY, Chen WC. Vascular endothelial growth factor gene-460 C/T polymorphism is a biomarker for prostate cancer. Urology. 2003. 62:374–377.

12. Ku KT, Wan L, Peng HC, Tsai MH, Tsai CH, Tsai FJ. Vascular endothelial growth factor gene-460 C/T polymorphism is a biomarker for oral cancer. Oral Oncol. 2005. 41:497–502.

13. Han SW, Kim GW, Seo JS, Kim SJ, Sa KH, Park JY, Lee J, Kim SY, Goronzy JJ, Weyand CM, Kang YM. VEGF gene polymorphisms and susceptibility to rheumatoid arthritis. Rheumatology (Oxford). 2004. 43:1173–1177.

14. Salvarani C, Boiardi L, Casali B, Olivieri I, Cantini F, Salvi F, Malatesta R, La Corte R, Triolo G, Ferrante A, Filippini D, Paolazzi G, Sarzi-Puttini P, Nicoli D, Farnetti E, Chen Q, Pulsatelli L. Vascular endothelial growth factor gene polymorphisms in Behcet's disease. J Rheumatol. 2004. 31:1785–1789.

15. Hamilton SR, Aaltnen LA, editors. WHO Classification of Tumours: Pathology and Genetics of Tumours of Digestive System. 2000. Geneva, Switzerland: WHO.

16. Greene FL. TNM staging for malignancies of the digestive tract: 2003 changes and beyond. Semin Surg Oncol. 2003. 21:23–29.

17. Xiao W, Oefner PJ. Denaturing high-performance liquid chromatography: a review. Hum Mutat. 2001. 17:439–474.

18. Kosaki K, Udaka T, Okuyama T. DHPLC in clinical molecular diagnostic services. Mol Genet Metab. 2005. 86:117–123.

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

20. Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, Inoue I, Katayama S. A common polymorphism in the 5' untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes. 2002. 51:1635–1639.

21. Langsenlehner U, Wolf G, Langsenlehner T, Gerger A, Hofmann G, Clar H, Wascher TC, Paulweber B, Samonigg H, Krippl P, Renner W. Genetic polymorphisms in the vascular endothelial growth factor gene and breast cancer risk. The Austrian "tumor of breast tissue: incidence, genetics, and environmental risk factors" study. Breast Cancer Res Treat. 2008. 109:297–304.

22. McCarron SL, Edwards S, Evans PR, Gibbs R, Dearnaley DP, Dowe A, Southgate C, Easton DF, Eeles RA, Howell WM. Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res. 2002. 62:3369–3372.

23. Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Haas J, Samonigg H. A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. Int J Cancer. 2003. 106:468–471.

24. Tzanakis N, Gazouli M, Rallis G, Giannopoulos G, Papaconstantinou I, Theodoropoulos G, Pikoulis E, Tsigris C, Karakitsos P, Peros G, Nikiteas N. Vascular endothelial growth factor polymorphism in gastric cancer development, prognosis, and survival. J Surg Oncol. 2006. 94:624–630.

25. Lee SJ, Lee SY, Jeon HS, Park SH, Jang JS, Lee GY, Son JW, Kim CH, Lee WK, Kam S, Park RW, Park TI, Kang YM, Kim IS, Jung TH, Park JY. Vascular endothelial growth factor gene polymorphisms and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev. 2005. 14:571–575.

26. Awata T, Kurihara S, Takata N, Neda T, Iizuka H, Ohkubo T, Osaki M, Watanabe M, Nakashima Y, Inukai K, Inoue I, Kawasaki I, Mori K, Yoneya S, Katayama S. Functional VEGF C-634G polymorphism is associated with development of diabetic macular edema and correlated with macular retinal thickness in type 2 diabetes. Biochem Biophys Res Commun. 2005. 333:679–685.

27. Koukourakis MI, Papazoglou D, Giatromanolaki A, Bougioukas G, Maltezos E, Sivridis E. VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer. 2004. 46:293–298.

28. Renner W, Kotschan S, Hoffmann C, Obermayer-Pietsch B, Pilger E. A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. J Vasc Res. 2000. 37:443–448.

29. Stevens A, Soden J, Brenchley PE, Ralph S, Ray DW. Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter. Cancer Res. 2003. 63:812–816.