Tumor Biology

, Volume 36, Issue 11, pp 8645–8652 | Cite as

Predictive value of vascular endothelial growth factor polymorphisms on the risk of renal cell carcinomas: a case–control study

  • Guangjian Lu
  • Yuqian Dong
  • Qunmei Zhang
  • Luyang Jiao
  • Shujuan Yang
  • Beili Shen
Research Article


We conducted this case–control study to assess the role of vascular endothelial growth factor (VEGF) −2578C/A, +460T/C, +1612G/A, +936C/T, and −634G/C polymorphisms in the development of renal cell carcinoma (RCC), and analyzed the association of gene polymorphisms with demographic and clinical characteristics of RCC. This study included 412 consecutive primary RCC patients and 824 controls. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to detect VEGF −2578C/A, +460T/C, +1612G/A, +936C/T, and −634G/C polymorphisms. Compared with the control subjects, the RCC cancer cases were more likely to have a habit of cigarette smoking, and suffered from hypertension and diabetes. Conditional logistic regression analysis showed that individuals carrying the AA genotype of −2578C/A were more likely to greatly increase risk of RCC, and the CC genotype of +460T/C revealed a significant association with increased risk of RCC. The CA + AA genotype of −2578C/A had a significantly increased risk of RCC in ever cigarette smokers, and individuals who suffered from hypertension and diabetes. TC + CC genotype of +460T/C was significantly associated with the elevated risk of RCC in those suffered from hypertension and diabetes. Our study suggests that −2578C/A and +460T/C polymorphisms of VEGF modulate the risk of developing RCC in Chinese population.


Vascular endothelial growth factor Polymorphism Renal cell carcinomas Cancer risk 


Conflicts of interest



  1. 1.
    GLOBOCAN. Estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer. 2012.
  2. 2.
    Vineis P, Alavanja M, Buffler P, Fontham E, Franceschi S, Gao YT, et al. Tobacco and cancer: recent epidemiological evidence. J Natl Cancer Inst. 2004;96(2):99–106.CrossRefPubMedGoogle Scholar
  3. 3.
    Bellocco R, Pasquali E, Rota M, Bagnardi V, Tramacere I, Scotti L, et al. Alcohol drinking and risk of renal cell carcinoma: results of a meta-analysis. Ann Oncol. 2012;23(9):2235–44.CrossRefPubMedGoogle Scholar
  4. 4.
    Adams KF, Leitzmann MF, Albanes D, Kipnis V, Moore SC, Schatzkin A, et al. Body size and renal cell cancer incidence in a large US cohort study. Am J Epidemiol. 2008;168(3):268–77. doi: 10.1093/aje/kwn122. Epub 2008 Jun 9.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Facchini F, Chen YD, Reaven GM. Light-to-moderate alcohol intake is associated with enhanced insulin sensitivity. Diabetes Care. 1994;17(2):115–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Mu HJ, Zou J, Xie P, Xu ZQ, Ruan J, Yang SD, et al. Association of leptin receptor Lys109Arg and Gln223Arg polymorphisms with increased risk of clear cell renal cell carcinoma. Asian Pac J Cancer Prev. 2014;15(10):4211–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Ou C, Zhao HL, Zhu B, Huang LS, Li PZ, Lao M. Association of vitamin D receptor gene polymorphism with the risk of renal cell carcinoma: a meta-analysis. J Recept Signal Transduct Res. 2014;19:1–6.Google Scholar
  8. 8.
    Atilgan D, Parlaktas BS, Uluocak N, Kolukcu E, Erdemir F, Ozyurt H, et al. The relationship between ALA16VAL single gene polymorphism and renal cell carcinoma. Adv Urol. 2014;2014:932481.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Barbera-Guillem E, Nyhus JK, Wolford CC, Friece CR, Sampsel JW. Vascular endothelial growth factor secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process. Cancer Res. 2002;62(23):7042–9.PubMedGoogle Scholar
  10. 10.
    Evensen L, Micklem DR, Blois A, Berge SV, Aarsaether N, Littlewood-Evans A, et al. Mural cell associated VEGF is required for organotypic vessel formation. PLoS One. 2009;4(6), e5798. doi: 10.1371/journal.pone.0005798.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002;2(10):795–803.CrossRefPubMedGoogle Scholar
  12. 12.
    Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23(5):1011–27.CrossRefPubMedGoogle Scholar
  13. 13.
    Andersen S, Donnem T, Al-Shibli K, Al-Saad S, Stenvold H, Busund LT, et al. Prognostic impacts of angiopoietins in NSCLC tumor cells and stroma: VEGF-A impact is strongly associated with Ang-2. PLoS One. 2011;6(5):e19773. doi: 10.1371/journal.pone.0019773.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    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(8):1232–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Ruggiero D, Dalmasso C, Nutile T, Sorice R, Dionisi L, Aversano M, et al. Genetics of VEGF serum variation in human isolated populations of cilento: importance of VEGF polymorphisms. PLoS One. 2011;6(2):e16982. doi: 10.1371/journal.pone.0016982.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Rinck-Junior JA, Oliveira C, Lourenço GJ, Sagarra RA, Derchain SF, Segalla JG, et al. Vascular endothelial growth factor (VEGF) polymorphism and increased risk of epithelial ovarian cancer. J Cancer Res Clin Oncol. 2014;93(8):1363–9.Google Scholar
  17. 17.
    Martinez-Fierro ML, Garza-Veloz I, Rojas-Martinez A, Ortiz-Lopez R, Castruita-de la Rosa C, Ortiz-Castro Y, et al. Positive association between vascular endothelial growth factor (VEGF) -2578 C/A variant and prostate cancer. Cancer Biomark. 2013;13(4):235–41. doi: 10.3233/CBM-130348.CrossRefPubMedGoogle Scholar
  18. 18.
    Wang Z, Wen P, Luo X, Fang X, Wang Q, Ma F, et al. Association of the vascular endothelial growth factor (VEGF) gene single-nucleotide polymorphisms with osteosarcoma susceptibility in a Chinese population. Tumour Biol. 2014;35(4):3605–10. doi: 10.1007/s13277-013-1475-7. Epub 2013 Dec 6.CrossRefPubMedGoogle Scholar
  19. 19.
    Sa-Nguanraksa D, Kooptiwut S, Chuangsuwanich T, Pongpruttipan T, Malasit P, O-Charoenrat P. Vascular endothelial growth factor polymorphisms affect gene expression and tumor aggressiveness in patients with breast cancer. Mol Med Rep. 2014;9(3):1044–8. doi: 10.3892/mmr.2014.1890.PubMedGoogle Scholar
  20. 20.
    Ajaz S, Khaliq S, Abid A, Hassan AS, Hashmi A, Sultan G, et al. Association of a single-nucleotide polymorphism in the promoter region of the VEGF gene with the risk of renal cell carcinoma. Genet Test Mol Biomarkers. 2011;15(9):653–7. doi: 10.1089/gtmb.2011.0029. Epub 2011 Apr 14.CrossRefPubMedGoogle Scholar
  21. 21.
    Sáenz-López P, Vazquez F, Cozar JM, Carretero R, Garrido F, Ruiz-Cabello F. VEGF polymorphisms are not associated with an increased risk of developing renal cell carcinoma in Spanish population. Hum Immunol. 2013;74(1):98–103. doi: 10.1016/j.humimm.2012.10.014. Epub 2012 Oct 13.CrossRefPubMedGoogle Scholar
  22. 22.
    Bruyère F, Hovens CM, Marson MN, d'Arcier BF, Costello AJ, Watier H, et al. VEGF polymorphisms are associated with an increasing risk of developing renal cell carcinoma. J Urol. 2010;184(4):1273–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Zhang Y, Li S, Xiao HQ, Hu ZX, Xu YC, Huang Q. Vascular endothelial growth factor gene polymorphisms and renal cell carcinoma: a systematic review and meta-analysis. Oncol Lett. 2013;6(4):1068–78. Epub 2013 Jul 29.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Ficarra V, Martignoni G, Maffei N, Brunelli M, Novara G, Zanolla L, et al. Original and reviewed nuclear grading according to the Fuhrman system: a multivariate analysis of 388 patients with conventional renal cell carcinoma. Cancer. 2005;103(1):68–75.CrossRefPubMedGoogle Scholar
  25. 25.
    Kushner EJ, Bautch VL. Building blood vessels in development and disease. Curr Opin Hematol. 2013;20(3):231–6. doi: 10.1097/MOH.0b013e328360614b.PubMedGoogle Scholar
  26. 26.
    Roy H, Bhardwaj S, Ylä-Herttuala S. Biology of vascular endothelial growth factors. FEBS Lett. 2006;580(12):2879–87. Epub 2006 Apr 17.CrossRefPubMedGoogle Scholar
  27. 27.
    Iordache S, Saftoiu A, Georgescu CV, et al. Vascular endothelial growth factor expression and microvessel density—two useful tools for the assessment of prognosis and survival in gastric cancer patients. J Gastrointestin Liver Dis. 2010;19:135–9.PubMedGoogle Scholar
  28. 28.
    Perrone G, Vincenzi B, Santini D, et al. Correlation of p53 and bcl-2 expression with vascular endothelial growth factor (VEGF), microvessel density (MVD) and clinicopathological features in colon cancer. Cancer Lett. 2004;208:227–34.CrossRefPubMedGoogle Scholar
  29. 29.
    Stefanou D, Batistatou A, Kamina S, et al. Expression of vascular endothelial growth factor (VEGF) and association with microvessel density in benign prostatic hyperplasia and prostate cancer. In Vivo. 2004;18:155–60.PubMedGoogle Scholar
  30. 30.
    Stathopoulou MG, Bonnefond A, Ndiaye NC, Azimi-Nezhad M, El Shamieh S, Saleh A, et al. A common variant highly associated with plasma VEGFA levels also contributes to the variation of both LDL-C and HDL-C. J Lipid Res. 2013;54(2):535–41. doi: 10.1194/jlr.P030551.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Rahoui J, Laraqui A, Sbitti Y, Touil N, Ibrahimi A, Ghrab B, et al. Investigating the association of vascular endothelial growth factor polymorphisms with breast cancer: a Moroccan case–control study. Med Oncol. 2014;31(9):193. doi: 10.1007/s12032-014-0193-3. Epub 2014 Aug 23.CrossRefPubMedGoogle Scholar
  32. 32.
    Maltese P, Canestrari E, Ruzzo A, Graziano F, Falcone A, Loupakis F, et al. VEGF gene polymorphisms and susceptibility to colorectal cancer disease in Italian population. Int J Colorectal Dis. 2009;24(2):165–70. doi: 10.1007/s00384-008-0586-x. Epub 2008 Oct 2.CrossRefPubMedGoogle Scholar
  33. 33.
    Jaiswal PK, Tripathi N, Shukla A, Mittal RD. Association of single nucleotide polymorphisms in vascular endothelial growth factor gene with bladder cancer risk. Med Oncol. 2013;30(2):509. doi: 10.1007/s12032-013-0509-8. Epub 2013 Feb 21.CrossRefPubMedGoogle Scholar
  34. 34.
    Xu Y, Zhu S. Associations between vascular endothelial growth factor polymorphisms and prostate cancer risk: a meta-analysis. Tumour Biol. 2014;35(2):1307–11. doi: 10.1007/s13277-013-1173-5. Epub 2013 Oct 15.CrossRefPubMedGoogle Scholar
  35. 35.
    Sa-Nguanraksa D, Chuangsuwanich T, Pongpruttipan T, Kummalue T, Rojananin S, Ratanawichhitrasin A, et al. Vascular endothelial growth factor ‑634G/C polymorphism is associated with increased breast cancer risk and aggressiveness. Mol Med Rep. 2013;8(4):1242–50. doi: 10.3892/mmr.2013.1607. Epub 2013 Jul 31.PubMedGoogle Scholar
  36. 36.
    Supic G, Jovic N, Zeljic K, Kozomara R, Magic Z. Association of VEGF-A genetic polymorphisms with cancer risk and survival in advanced-stage oral squamous cell carcinoma patients. Oral Oncol. 2012;48(11):1171–7. doi: 10.1016/j.oraloncology.2012.05.023. Epub 2012 Jul 18.CrossRefPubMedGoogle Scholar
  37. 37.
    Hong TT, Cai DY, Wu XH, Hua D. Three vascular endothelial growth factor polymorphisms (−460C > T, −2578C > A, 1612G > A) with cancer risk: a meta-analysis based on 30 case–control studies. Cancer Invest. 2011;29(7):472–7. doi: 10.3109/07357907.2011.597811.PubMedGoogle Scholar
  38. 38.
    Conklin BS, Zhao W, Zhong DS, Chen C. Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells. Am J Pathol. 2002;160(2):413–8.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kanda Y, Watanabe Y. Nicotine-induced vascular endothelial growth factor release via the EGFR-ERK pathway in rat vascular smooth muscle cells. Life Sci. 2007;80(15):1409–14. Epub 2007 Jan 17.CrossRefPubMedGoogle Scholar
  40. 40.
    Wong HP, Yu L, Lam EK, Tai EK, Wu WK, Cho CH. Nicotine promotes colon tumor growth and angiogenesis through beta-adrenergic activation. Toxicol Sci. 2007;97(2):279–87. Epub 2007 Mar 16.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Guangjian Lu
    • 1
  • Yuqian Dong
    • 1
  • Qunmei Zhang
    • 2
  • Luyang Jiao
    • 1
  • Shujuan Yang
    • 3
  • Beili Shen
    • 4
  1. 1.Clinical LaboratoryThe First Affiliated Hospital of Xinxiang Medical UniversityWeihuiChina
  2. 2.Blood Transfusion RoomThe First Affiliated Hospital of Xinxiang Medical UniversityWeihuiChina
  3. 3.Department of Health and Social Behavior, West China School of Public HealthSichuan UniversityChengduChina
  4. 4.Department of Renal TransplantationZhengzhou People’s HospitalZhengzhouChina

Personalised recommendations