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Systematic review and meta-analysis on vitamin D receptor polymorphisms and cancer risk

Tumor Biology volume 35, pages 4153–4169 (2014)Cite this article

Abstract

The vitamin D receptor (VDR) can influence cancer susceptibility through binding to vitamin D. However, the previous studies were contradictory. Therefore this meta-analysis was conducted to clarify the association between VDR polymorphisms (BsmI, TaqI, FokI, and ApaI) and cancer risk. One hundred twenty-six studies were enrolled through PubMed. For VDR BsmI polymorphism, significantly increased cancer risks were observed in the overall analysis. In the further stratified analysis, increased risks were observed in colorectal and skin cancer, especially in Caucasian population. However, no significant associations were observed in other VDR polymorphisms in the overall analysis. In the further subgroup analysis, increased risks were found in oral, breast, and basal cell cancer while decreased risk was found in prostate cancer in t allele carriers of TaqI polymorphism. For VDR FokI polymorphism, increased risks were found in ovarian and skin cancer while decreased risk in glioma in f allele carriers. For VDR ApaI polymorphism, increased risk was observed in basal cell cancer, especially in Asian population in a allele carriers. In conclusion, these results indicated that b allele of BamI polymorphism was a risk factor for cancer susceptibility. Meanwhile, t allele of TaqI polymorphism was a risk factor for oral, breast, and basal cell cancer and a protective factor for prostate cancer. Moreover, f allele of FokI polymorphism was a risk factor for ovarian and skin cancer and a protective factor for glioma. Finally, a allele of ApaI polymorphism was a risk factor for basal cell cancer in Asian population.

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References

  1. Bertone-Johnson ER. Vitamin D, and breast cancer. Ann Epidemiol. 2009;19(7):462–7. doi:10.1016/j.annepidem.2009.01.003.

    Article  PubMed  Google Scholar 

  2. Manolagas SC, Yu XP, Girasole G, Bellido T. Vitamin D and the hematolymphopoietic tissue: a 1994 update. Semin Nephrol. 1994;14(2):129–43.

    CAS  PubMed  Google Scholar 

  3. Deeb KK, Trump DL, Johnson CS. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer. 2007;7(9):684–700. doi:10.1038/nrc2196.

    CAS  Article  PubMed  Google Scholar 

  4. Norman AW. Minireview: vitamin D receptor: new assignments for an already busy receptor. Endocrinology. 2006;147(12):5542–8. doi:10.1210/en.2006-0946.

    CAS  Article  PubMed  Google Scholar 

  5. Raimondi S, Johansson H, Maisonneuve P, Gandini S. Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Carcinogenesis. 2009;30(7):1170–80. doi:10.1093/carcin/bgp103.

    CAS  Article  PubMed  Google Scholar 

  6. Zmuda JM, Cauley JA, Ferrell RE. Molecular epidemiology of vitamin D receptor gene variants. Epidemiol Rev. 2000;22(2):203–17.

    CAS  Article  PubMed  Google Scholar 

  7. Whitfield GK, Remus LS, Jurutka PW, Zitzer H, Oza AK, Dang HT, et al. Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol. 2001;177(1–2):145–59.

    CAS  Article  PubMed  Google Scholar 

  8. Miyamoto K, Kesterson RA, Yamamoto H, Taketani Y, Nishiwaki E, Tatsumi S, et al. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol. 1997;11(8):1165–79.

    CAS  Article  PubMed  Google Scholar 

  9. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004;338(2):143–56. doi:10.1016/j.gene.2004.05.014.

    CAS  Article  PubMed  Google Scholar 

  10. Mocellin S, Nitti D. Vitamin D receptor polymorphisms and the risk of cutaneous melanoma: a systematic review and meta-analysis. Cancer. 2008;113(9):2398–407. doi:10.1002/cncr.23867.

    Article  PubMed  Google Scholar 

  11. Colin EM, Weel AE, Uitterlinden AG, Buurman CJ, Birkenhager JC, Pols HA, et al. Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1, 25-dihydroxyvitamin D3. Clin Endocrinol (Oxf). 2000;52(2):211–6.

    CAS  Article  PubMed  Google Scholar 

  12. Mishra DK, Wu Y, Sarkissyan M, Sarkissyan S, Chen Z, Shang X, et al. Vitamin D receptor gene polymorphisms and prognosis of breast cancer among African-American and Hispanic women. PLoS One. 2013;8(3):e57967. doi:10.1371/journal.pone.0057967.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Fuhrman BJ, Freedman DM, Bhatti P, Doody MM, Fu YP, Chang SC, et al. Sunlight, polymorphisms of vitamin D-related genes and risk of breast cancer. Anticancer Res. 2013;33(2):543–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Shahbazi S, Alavi S, Majidzadeh AK, Ghaffarpour M, Soleimani A, Mahdian R. BsmI but not FokI polymorphism of VDR gene is contributed in breast cancer. Med Oncol. 2013;30(1):393. doi:10.1007/s12032-012-0393-7.

    Article  PubMed  Google Scholar 

  15. Holt SK, Kwon EM, Peters U, Ostrander EA, Stanford JL. Vitamin D pathway gene variants and prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2009;18(6):1929–33. doi:10.1158/1055-9965.EPI-09-0113.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Holick CN, Stanford JL, Kwon EM, Ostrander EA, Nejentsev S, Peters U. Comprehensive association analysis of the vitamin D pathway genes, VDR, CYP27B1, and CYP24A1, in prostate cancer. Cancer Epidemiol Biomarkers Prev. 2007;16(10):1990–9. doi:10.1158/1055-9965.EPI-07-0487.

    CAS  Article  PubMed  Google Scholar 

  17. Li H, Stampfer MJ, Hollis JB, Mucci LA, Gaziano JM, Hunter D, et al. A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer. PLoS Med. 2007;4(3):e103. doi:10.1371/journal.pmed.0040103.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Jenab M, McKay J, Bueno-de-Mesquita HB, van Duijnhoven FJ, Ferrari P, Slimani N, et al. Vitamin D receptor and calcium sensing receptor polymorphisms and the risk of colorectal cancer in European populations. Cancer Epidemiol Biomarkers Prev. 2009;18(9):2485–91. doi:10.1158/1055-9965.EPI-09-0319.

    CAS  Article  PubMed  Google Scholar 

  19. Slattery ML, Murtaugh M, Caan B, Ma KN, Wolff R, Samowitz W. Associations between BMI, energy intake, energy expenditure, VDR genotype and colon and rectal cancers (United States). Cancer Causes Control. 2004;15(9):863–72. doi:10.1007/s10552-004-1048-6.

    Article  PubMed  Google Scholar 

  20. Kim HS, Newcomb PA, Ulrich CM, Keener CL, Bigler J, Farin FM, et al. Vitamin D receptor polymorphism and the risk of colorectal adenomas: evidence of interaction with dietary vitamin D and calcium. Cancer Epidemiol Biomarkers Prev. 2001;10(8):869–74.

    CAS  PubMed  Google Scholar 

  21. Mostowska A, Sajdak S, Pawlik P, Lianeri M, Jagodzinski PP. Vitamin D receptor gene BsmI and FokI polymorphisms in relation to ovarian cancer risk in the Polish population. Genet Test Mol Biomarkers. 2013;17(3):183–7. doi:10.1089/gtmb.2012.0332.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Grant DJ, Hoyo C, Akushevich L, Iversen ES, Whitaker R, Marks J, et al. Vitamin D receptor (VDR) polymorphisms and risk of ovarian cancer in Caucasian and African American women. Gynecol Oncol. 2013;129(1):173–8. doi:10.1016/j.ygyno.2012.12.027.

    CAS  Article  PubMed  Google Scholar 

  23. Tworoger SS, Gates MA, Lee IM, Buring JE, Titus-Ernstoff L, Cramer D, et al. Polymorphisms in the vitamin D receptor and risk of ovarian cancer in four studies. Cancer Res. 2009;69(5):1885–91. doi:10.1158/0008-5472.CAN-08-3515.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    CAS  Article  PubMed  Google Scholar 

  25. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719–48.

    CAS  PubMed  Google Scholar 

  26. Campbell MJ, Elstner E, Holden S, Uskokovic M, Koeffler HP. Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin. J Mol Endocrinol. 1997;19(1):15–27.

    CAS  Article  PubMed  Google Scholar 

  27. Ylikomi T, Laaksi I, Lou YR, Martikainen P, Miettinen S, Pennanen P, et al. Antiproliferative action of vitamin D. Vitam Horm. 2002;64:357–406.

    CAS  Article  PubMed  Google Scholar 

  28. Kinyamu HK, Gallagher JC, Knezetic JA, DeLuca HF, Prahl JM, Lanspa SJ. Effect of vitamin D receptor genotypes on calcium absorption, duodenal vitamin D receptor concentration, and serum 1,25 dihydroxyvitamin D levels in normal women. Calcif Tissue Int. 1997;60(6):491–5.

    CAS  Article  PubMed  Google Scholar 

  29. Mocharla H, Butch AW, Pappas AA, Flick JT, Weinstein RS, De Togni P, et al. Quantification of vitamin D receptor mRNA by competitive polymerase chain reaction in PBMC: lack of correspondence with common allelic variants. J Bone Miner Res. 1997;12(5):726–33. doi:10.1359/jbmr.1997.12.5.726.

    CAS  Article  PubMed  Google Scholar 

  30. Gross C, Musiol IM, Eccleshall TR, Malloy PJ, Feldman D. Vitamin D receptor gene polymorphisms: analysis of ligand binding and hormone responsiveness in cultured skin fibroblasts. Biochem Biophys Res Commun. 1998;242(3):467–73. doi:10.1006/bbrc.1997.7986.

    CAS  Article  PubMed  Google Scholar 

  31. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, et al. Prediction of bone density from vitamin D receptor alleles. Nature. 1994;367(6460):284–7. doi:10.1038/367284a0.

    CAS  Article  PubMed  Google Scholar 

  32. Chudek J, Karkoszka H, Schmidt-Gayk H, Ritz E, Kokot F. Plasma parathyroid hormone, phosphatemia and vitamin D receptor genotype: are they interrelated? J Nephrol. 2000;13(1):54–8.

    CAS  PubMed  Google Scholar 

  33. Bai YH, Lu H, Hong D, Lin CC, Yu Z, Chen BC. Vitamin D receptor gene polymorphisms and colorectal cancer risk: a systematic meta-analysis. World J Gastroenterol. 2012;18(14):1672–9. doi:10.3748/wjg.v18.i14.1672.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Gross C, Eccleshall TR, Malloy PJ, Villa ML, Marcus R, Feldman D. The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women. J Bone Miner Res. 1996;11(12):1850–5. doi:10.1002/jbmr.5650111204.

    CAS  Article  PubMed  Google Scholar 

  35. Orlow I, Roy P, Reiner AS, Yoo S, Patel H, Paine S, et al. Vitamin D receptor polymorphisms in patients with cutaneous melanoma. Int J Cancer. 2012;130(2):405–18. doi:10.1002/ijc.26023.

    CAS  Article  PubMed  Google Scholar 

  36. Han J, Colditz GA, Hunter DJ. Polymorphisms in the MTHFR and VDR genes and skin cancer risk. Carcinogenesis. 2007;28(2):390–7. doi:10.1093/carcin/bgl156.

    CAS  Article  PubMed  Google Scholar 

  37. Haussler MR, Whitfield GK, Haussler CA, Hsieh JC, Thompson PD, Selznick SH, et al. The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res. 1998;13(3):325–49. doi:10.1359/jbmr.1998.13.3.325.

    CAS  Article  PubMed  Google Scholar 

  38. Liu Y, Li C, Chen P, Li X, Li M, Guo H, et al. Polymorphisms in the vitamin D receptor (VDR) and the risk of ovarian cancer: a meta-analysis. PLoS One. 2013;8(6):e66716. doi:10.1371/journal.pone.0066716.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Jurutka PW, Whitfield GK, Hsieh JC, Thompson PD, Haussler CA, Haussler MR. Molecular nature of the vitamin D receptor and its role in regulation of gene expression. Rev Endocr Metab Disord. 2001;2(2):203–16.

    CAS  Article  PubMed  Google Scholar 

  40. Xu L, Glass CK, Rosenfeld MG. Coactivator and corepressor complexes in nuclear receptor function. Curr Opin Genet Dev. 1999;9(2):140–7. doi:10.1016/S0959-437X(99)80021-5.

    CAS  Article  PubMed  Google Scholar 

  41. Abbas S, Nieters A, Linseisen J, Slanger T, Kropp S, Mutschelknauss EJ, et al. Vitamin D receptor gene polymorphisms and haplotypes and postmenopausal breast cancer risk. Breast Cancer Res. 2008;10(2):R31. doi:10.1186/bcr1994.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Guo YJ, Shi ZM, Liu JD, Lei N, Chen QH, Tang Y. Meta-analysis of the relation between the VDR gene TaqI polymorphism and genetic susceptibility to prostate cancer in Asian populations. Asian Pac J Cancer Prev. 2012;13(9):4441–4.

    Article  PubMed  Google Scholar 

  43. Bektas-Kayhan K, Unur M, Yaylim-Eraltan I, Ergen HA, Toptas B, Hafiz G, et al. Association of vitamin D receptor TaqI polymorphism and susceptibility to oral squamous cell carcinoma. In Vivo. 2010;24(5):755–9.

    CAS  PubMed  Google Scholar 

  44. Tang C, Chen N, Wu M, Yuan H, Du Y. Fok1 polymorphism of vitamin D receptor gene contributes to breast cancer susceptibility: a meta-analysis. Breast Cancer Res Treat. 2009;117(2):391–9. doi:10.1007/s10549-008-0262-4.

    CAS  Article  PubMed  Google Scholar 

  45. Arai H, Miyamoto K, Taketani Y, Yamamoto H, Iemori Y, Morita K, et al. A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res. 1997;12(6):915–21. doi:10.1359/jbmr.1997.12.6.915.

    CAS  Article  PubMed  Google Scholar 

  46. Anic GM, Thompson RC, Nabors LB, Olson JJ, Browning JE, Madden MH, et al. An exploratory analysis of common genetic variants in the vitamin D pathway including genome-wide associated variants in relation to glioma risk and outcome. Cancer Causes Control. 2012;23(9):1443–9. doi:10.1007/s10552-012-0018-7.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Clendenen TV, Arslan AA, Koenig KL, Enquist K, Wirgin I, Agren A, et al. Vitamin D receptor polymorphisms and risk of epithelial ovarian cancer. Cancer Lett. 2008;260(1–2):209–15. doi:10.1016/j.canlet.2007.11.002.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Program of Healthy Talents’ Cultivation for Nanjing City, and Social Development Technology Projects of Nanjing City, China (QYK11175).

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Affiliations

  1. Central Laboratory of Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China

    Yeqiong Xu, Bangshun He, Yuqin Pan, Qiwen Deng, Tianyi Gao, Guoqi Song & Shukui Wang

  2. Department of Life Sciences, Nanjing Normal University, Nanjing, China

    Huiling Sun & Rui Li

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  1. Yeqiong Xu
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  2. Bangshun He
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Correspondence to Shukui Wang.

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Yeqiong Xu and Bangshun He contributed equally to this work.

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Xu, Y., He, B., Pan, Y. et al. Systematic review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Tumor Biol. 35, 4153–4169 (2014). https://doi.org/10.1007/s13277-013-1544-y

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Keywords

  • Vitamin D receptor
  • VDR
  • Polymorphism
  • Cancer risk