Tumor Biology

, Volume 36, Issue 1, pp 375–381 | Cite as

Genetic variants of chemokine CCL2 and chemokine receptor CCR2 genes and risk of prostate cancer

  • Raju K. Mandal
  • Toshi Agrawal
  • Rama Devi Mittal
Research Article


Chemokines and their receptors acts as mediators of migration of immune cells to the site of inflammation and deregulated inflammatory response is associated with increased risk of cancer. We performed a case-control study to analyze the frequencies of CCL2 (I/D, rs3917887), -2518 (A > G, rs1024611), and CCR2 (G > A, rs1799864) polymorphisms for prostate cancer (PCa) risk. In this hospital-based case-control study, histologically confirmed 195 PCa patients and 250 unrelated healthy controls of similar ethnicity were genotyped by PCR-RFLP. The result showed that heterozygous ID (odds ratio (OR) = 1.71; p = 0.010) carrier genotype of CCL2 gene were at increased risk for developing PCa. Variant allele D carriers (ID + DD) demonstrated a 1.67-fold increased risk (OR = 1.67; p = 0.010), suggesting a dominant effect model involved in PCa risk. Similarly, variant allele D of CCL2 gene also had a higher risk (OR = 1.53; p = 0.040) for developing PCa. High risk to PCa was also observed with respect to diplotypes, I-G (OR = 1.83; Bonferroni corrected p value (P c) = 0.004) and D-A (OR = 2.11; P c = 0.004) of CCL2 I/D and -2518 (A > G). In association of genotypes with clinic-pathological grade of tumor, homozygous DD (OR = 7.40; P c = 0.042) and variant allele carrier ID + DD (OR = 2.42; P c = 0.036) genotypes of CCL2 gene conferred risk in high Gleason grade tumor of PCa. We observed a significantly enhanced risk for PCa due to interaction between CCL2 I/D, -2518 (A > G), and CCR2 (G > A) genotypes. However, -2518 (A > G) and CCR2 V64I (G > A) gene polymorphisms were not significantly associated with PCa risk. Our results supported that CCL2 I/D gene variant contribute to the susceptibility and clinic-pathological characteristic of PCa and could be considered as an important risk factor for this malignancy in North Indian men.


Inflammatory genes Polymorphism Prostate cancer Gene-gene interaction 


Conflicts of interest



  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Patel AR, Klein EA. Risk factors for prostate cancer. Nat Clin Pract Urol. 2009;6:87–95.CrossRefPubMedGoogle Scholar
  3. 3.
    Thomas G, Jacobs KB, Yeager M, Kraft P, Wacholder S, et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet. 2008;40:310–5.CrossRefPubMedGoogle Scholar
  4. 4.
    Costantini S, Caone F, Guerriero E, Castello G. An approach for understanding the inflammation and cancer relationship. Immunol Lett. 2009;126:91–2.CrossRefPubMedGoogle Scholar
  5. 5.
    De Marzo AM, Marchi VL, Epstein JI, Nelson WG. Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol. 1999;155:1985–92.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bostwick DG, de la Roza G, Dundore P, Corica FA, Iczkowski KA. Intraepithelial and stromal lymphocytes in the normal human prostate. Prostate. 2003;55:187–93.CrossRefPubMedGoogle Scholar
  7. 7.
    Charo IF, Taubman MB. Chemokines in the pathogenesis of vascular disease. Circ Res. 2004;95:858–66.CrossRefPubMedGoogle Scholar
  8. 8.
    Loberg RD, Day LL, Harwood J, Ying C, St John LN, Giles R, et al. CCL2 is a potent regulator of prostate cancer cell migration and proliferation. Neoplasia. 2006;8:578–86.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Roca H, Varsos Z, Pienta KJ. CCL2 protects prostate cancer PC3 cells from autophagic death via phosphatidylinositol 3-kinase/AKT-dependent surviving up-regulation. J Biol Chem. 2008;283:25057–73.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chinoy H, Salway F, Fertig N, Tait BD, Oddis CV, Ollier WE, et al. Monocyte chemotactic protein-1 single nucleotide polymorphisms do not confer susceptibility for the development of adult onset polymyositis/dermatomyositis in UK Caucasians. Rheumatology (Oxford). 2006;46:604–7.CrossRefGoogle Scholar
  11. 11.
    Rovin BH, Lu L, Saxena R. A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression. Biochem Biophys Res Commun. 1999;259:3448.CrossRefGoogle Scholar
  12. 12.
    Zhang J, Patel L, Pienta KJ. CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. Cytokine Growth Factor Rev. 2010;21:41–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Craig MJ, Loberg RD. CCL2 (monocyte chemoattractant protein-1) in cancer bone metastases. Cancer Metastasis Rev. 2006;25:611–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Kostrikis LG, Huang Y, Moore JP, Wolinsky SM, Zhang L, Guo Y, et al. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nat Med. 1998;4:350–3.CrossRefPubMedGoogle Scholar
  15. 15.
    Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol. 1974;111:58–64.PubMedGoogle Scholar
  16. 16.
    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ahluwalia TS, Khullar M, Ahuja M, Kohli HS, Bhansali A, Mohan V, et al. Common variants of inflammatory cytokine genes are associated with risk of nephropathy in type 2 diabetes among Asian Indians. PLoS One. 2009;4:e5168.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Narter KF, Agachan B, Sozen S, Cincin ZB, Isbir T. CCR2-64I is a risk factor for development of bladder cancer. Genet Mol Res. 2010;9:685–92.CrossRefPubMedGoogle Scholar
  19. 19.
    Rodriguez S, Gaunt TR, Ian NMD. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169:505–14.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Faul F, Erdfelder E, Lang AG, Buchner A. G Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175.CrossRefPubMedGoogle Scholar
  21. 21.
    Mantovani A, Allavena P, Sica A, Balkwill F. Cancer related inflammation. Nature. 2008;454:436–44.CrossRefPubMedGoogle Scholar
  22. 22.
    Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4:540–50.CrossRefPubMedGoogle Scholar
  23. 23.
    Singh V, Srivastava P, Srivastava N, Kapoor R, Mittal RD. Association of inflammatory chemokine gene CCL2I/D with bladder cancer risk in North Indian population. Mol Biol Rep. 2012;39:9827–34.CrossRefPubMedGoogle Scholar
  24. 24.
    Lu Y, Cai Z, Galson DL, Xiao G, Liu Y, George DE, et al. Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. Prostate. 2006;66:1311–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Mazzucchelli L, Loetscher P, Kappeler A, Uguccioni M, Baggiolini M, Laissue JA, et al. Monocyte chemoattractant protein-1 gene expression in prostatic hyperplasia and prostate adenocarcinoma. Am J Pathol. 1996;149:501–19.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Li X, Loberg R, Liao J, Ying C, Snyder LA, Pienta KJ, et al. A destructive cascade mediated by CCL2 facilitates prostate cancer growth in bone. Cancer Res. 2009;69:1685–92.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Loberg RD, Ying C, Craig M, Yan L, Snyder LA, Pienta KJ. CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia. 2007;9:556–62.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Sáenz-López P, Carretero R, Cózar JM, Romero JM, Canton J, Vilchez JR, et al. Genetic polymorphisms of RANTES, IL1-A, MCP-1 and TNF-A genes in patients with prostate cancer. BMC Cancer. 2008;8:382.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kucukgergin C, Isman FK, Cakmakoglu B, Sanli O, Seckin S. Association of polymorphisms in MCP-1, CCR2, and CCR5 genes with the risk and clinicopathological characteristics of prostate cancer. DNA Cell Biol. 2012;31:1418–24.CrossRefPubMedGoogle Scholar
  30. 30.
    Vázquez-Lavista LG, Lima G, Gabilondo F, Llorente L. Genetic association of monocyte chemoattractant protein 1 (MCP-1) 2518 polymorphism in Mexican patients with transitional cell carcinoma of the bladder. Urology. 2009;74:414–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Liou JM, Lin JT, Huang SP, Wu CY, Wang HP, Lee YC, et al. RANTES-403 polymorphism is associated with reduced risk of gastric cancer in women. J Gastroenterol. 2008;43:115–23.CrossRefPubMedGoogle Scholar
  32. 32.
    Liu GX, Zhang X, Li S, Richard DK, Jerry H, Song H. Monocyte chemotactic protein-1 and CC chemokine receptor 2 polymorphisms and prognosis of renal cell carcinoma. Tumor Biol. 2013;34:2741–6.CrossRefGoogle Scholar
  33. 33.
    Chetcuti A, Margan S, Mann S, Russell P, Handelsman D, Rogers J, et al. Identification of differentially expressed genes in organ-confined prostate cancer by gene expression array. Prostate. 2011;47:132–40.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Raju K. Mandal
    • 1
  • Toshi Agrawal
    • 1
  • Rama Devi Mittal
    • 1
  1. 1.Department of Urology and Renal TransplantationSanjay Gandhi Post Graduate Institute of Medical SciencesLucknowIndia

Personalised recommendations