Vitamin D

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This section does not replicate the other information on this topic but provides additional details or context most relevant to professionals.

Improving bone mineral density behaviors

Men with prostate cancer receiving androgen deprivation therapy showed higher rate of bone mineral density testing when receiving both a patient bone health pamphlet and support from a bone health care coordinator compared to usual care. Men receiving a patient bone health pamphlet and brief recommendations for their family physician showed more use of calcium and vitamin D and orders of bone mineral density tests in a mid-sized RCT.¹Alibhai SMH, Breunis H et al. Improving bone health in men with prostate cancer receiving androgen deprivation therapy: results of a randomized phase 2 trial. Cancer. 2018 Mar sa15;124(6):1132-1140. 

Vitamin D receptor and gene polymorphisms

Genetic variants may influence the response of the vitamin D receptor (VDR) to vitamin D treatment.

Vitamin D effects as a whole

• Allelic variants were related to a higher transcription of VDR gene and a higher activity of VDR receptor.²Amadori D, Serra P et al. Vitamin D receptor polymorphisms or serum levels as key drivers of breast cancer development? The question of the vitamin D pathway. Oncotarget. 2017 Feb 21;8(8):13142-13156.
• A link among gene polymorphisms and diseases has been established.³Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. Clinica Chimica Acta. 2006 Sep;371(1-2):1-12. 

Cancer survival

• The protein expression level of VDR in entire breast cancer cells evaluated by immunohistochemistry is related to the overall survival of breast cancer patients.⁴Xu H, Liu Z, Shi H, Wang C. Prognostic role of vitamin D receptor in breast cancer: a systematic review and meta-analysis. BMC Cancer. 2020 Nov 1;20(1):1051. 
• Better survival among people with advanced non–small-cell lung cancer with the C/C genotype of the FokI polymorphism compared to C/T or T/T genotypes, although 25(OH)D levels had no main effect on survival, in a mid-sized observational study⁵Heist RS, Zhou W et al. Circulating 25-hydroxyvitamin D, VDR polymorphisms, and survival in advanced non-small-cell lung cancer. Journal of Clinical Oncology. 2008 Dec 1;26(34):5596-602.

Risk of recurrence

• Single nucleotide polymorphisms (SNPs) in retinoid-X receptor alpha (RXRA) may be a predictor for disease-free survival with breast cancer.⁶Pande M, Thompson PA et al. Genetic variants in the vitamin D pathway and breast cancer disease-free survival. Carcinogenesis. 2013 Mar;34(3):587-94.

Risk of cancer

Cancer as a whole

• The rs12785878, rs1790349, and rs12794714 SNPs related to vitamin D-metabolizing enzymes might potentially be biomarkers for cancer susceptibility.⁷Wen J, Li J, Liang X, Wang A. Association of polymorphisms in vitamin D-metabolizing enzymes DHCR7 and CYP2R1 with cancer susceptibility: a systematic review and meta-analysis. Disease Markers. 2021 May 22;2021:6615001.
• The rs4588 and rs7041 polymorphisms, related to vitamin D metabolism, were significantly associated with overall cancer risk. Stratification analyses of ethnicity indicated that rs4588 polymorphism significantly increased cancer risk in Caucasians and Asians, while rs7041 polymorphism significantly increased cancer risk in Asians.⁸Zhu M, Tan Z et al. Association of the vitamin D metabolism gene GC and CYP27B1 polymorphisms with cancer susceptibility: a meta-analysis and trial sequential analysis. Bioscience Reports. 2019 Sep 13;39(9):BSR20190368.
• The rs2585428 and rs4809960 polymorphisms, related to vitamin D degradation, were significantly associated with overall cancer risk.⁹Zhu M, Qiu S et al. The associations between CYP24A1 polymorphisms and cancer susceptibility: a meta-analysis and trial sequential analysis. Pathology, Research and Practice. 2018 Jan;214(1):53-63.
• Some differences were found, partially explained by minor allele frequency (MAF), for colorectal cancer, ovarian and prostate cancer in Caucasian and prostate cancer in Asian populations.¹⁰Gnagnarella P, Raimondi S et al. Ethnicity as modifier of risk for Vitamin D receptors polymorphisms: comprehensive meta-analysis of all cancer sites. Critical Reviews in Oncology/Hematology. 2021 Feb;158:103202.
• There is a correlation between the TaqI polymorphism of vitamin D receptor (VDR)  and the risk of tobacco-related cancers.¹¹Laczmanski L, Laczmanska I, Lwow F. Association of select vitamin D receptor gene polymorphisms with the risk of tobacco-related cancers—a meta-analysis. Scientific Reports. 2019 Nov 5;9(1):16026.

Breast cancer

• The rs4809960 SNP, related to vitamin D degradation, significantly decreased the risk of breast cancer.¹²Zhu M, Qiu S et al. The associations between CYP24A1 polymorphisms and cancer susceptibility: a meta-analysis and trial sequential analysis. Pathology, Research and Practice. 2018 Jan;214(1):53-63.
• VDR Bsm1, Apa1, Fok1, and Poly (A) gene polymorphisms may be susceptible for breast cancer development.¹³Iqbal MUN, Khan TA. Association between vitamin D receptor Cdx2, Fok1, Bsm1, Apa1, Bgl1, Taq1, and Poly (A) gene polymorphism and breast cancer: a systematic review and meta-analysis. Tumour Biology. 2017 Oct;39(10):1010428317731280.

Colorectal cancer

• Benefits from vitamin D₃ supplementation for the prevention of advanced colorectal adenomas may vary according to vitamin D receptor genotype.¹⁴Barry EL, Peacock JL et al. Vitamin D receptor genotype, vitamin D₃ supplementation, and risk of colorectal adenomas: a randomized clinical trial. Journal of the American Medical Association Oncology. 2017 May 1;3(5):628-635.
• The role of VDR FokI polymorphism may differ based on the type and severity of colorectal disease.¹⁵Cho YA, Lee J et al. Vitamin D receptor FokI polymorphism and the risks of colorectal cancer, inflammatory bowel disease, and colorectal adenoma. Scientific Reports. 2018 Aug 27;8(1):12899.

Gastrointestinal cancer

• VDR rs7975232, VDR rs2228570, VEGF rs699947, VEGF rs3025039, IL-18 rs1946518, and MBL rs7096206 polymorphisms may confer susceptibility to hepatocellular carcinoma in certain populations.¹⁶Quan Y, Yang J, Qin T, Hu Y. Associations between twelve common gene polymorphisms and susceptibility to hepatocellular carcinoma: evidence from a meta-analysis. World Journal of Surgical Oncology. 2019 Dec 12;17(1):216.

Gynecologic cancer

• The F variant reduces the risk of cancer by 4%. This effect is particularly evident in female sex-associated cancers, but it is not observed in non-sex-associated cancers.¹⁷Laczmanski L, Lwow F et al. Association of the vitamin D receptor FokI gene polymorphism with sex- and non-sex-associated cancers: a meta-analysis. Tumour Biology. 2017 Oct;39(10):1010428317727164.
• The VDR rs2228570 polymorphism increased the risk of ovarian cancer in Caucasian populations in a dominant genetic model.¹⁸Chen H, Zhu J. Vitamin D receptor rs2228570 polymorphism and susceptibility to ovarian cancer: an updated meta-analysis. Journal of Obstetrics and Gynaecology Research. 2018 Mar;44(3):556-565.

Kidney cancer

• The vitamin D receptor ApaI A allele, ApaI AA and aa genotypes, BsmI B allele, and Fok1 FF genotype are associated with renal cell carcinoma risk.¹⁹Zhou T, Li H et ak. Association of methylenetetrahydrofolate reductase, vitamin D receptor, and interleukin-16 gene polymorphisms with renal cell carcinoma risk. Technology in Cancer Research & Treatment. 2019 Jan 1;18:1533033819859413.

Lung cancer

• The VDR Bsm1 and Cdx2 polymorphisms decreased lung cancer risk, while the Taq1 polymorphism increased lung cancer risk. The AA genotype of the Apa1 and Bsm1 variants were protective factors in Asian populations, whereas the Fok1 and Taq1 polymorphisms were risk factors for lung cancer in Asian populations.²⁰Duan GQ, Zheng X et al. The association between VDR and GC polymorphisms and lung cancer risk: a systematic review and meta-analysis. Genetic Testing and Molecular Biomarkers. 2020 May;24(5):285-295.
• Lung cancer risk varies by vitamin D receptor (VDR) genetic polymorphism.²¹Yu ZH, Chen M, Zhang QQ, Hu X. The association of vitamin D receptor gene polymorphism with lung cancer risk: an update meta-analysis. Combinatorial Chemistry & High Throughput Screening. 2018;21(10):704-710.

Melanoma

• The VDR variants FokI, ApaI and BsmI may influence the susceptibility to developing melanoma.²²Birke M, Schöpe J, Wagenpfeil S, Vogt T, Reichrath J. Association of vitamin D receptor gene polymorphisms with melanoma risk: a meta-analysis and systematic review. Anticancer Research. 2020 Feb;40(2):583-595.

Pancreatic cancer

• The VDR rs2585428 SNP significantly decreased the risk of pancreas cancer.²³Zhu M, Qiu S et al. The associations between CYP24A1 polymorphisms and cancer susceptibility: a meta-analysis and trial sequential analysis. Pathology, Research and Practice. 2018 Jan;214(1):53-63.

Prostate cancer

• A significant association is seen between VDR rs731236 and prostate cancer risk in Asians and African Americans, but rs1544410 was not associated with prostate cancer under three genetic models.²⁴Liu S, Cai H et al. Association of VDR polymorphisms (Taq I and Bsm I) with prostate cancer: a new meta-analysis. Journal of International Medical Research. 2017 Feb;45(1):3-10.

Body terrain factors

• Genetic variants associated with low plasma 25(OH)D concentrations are associated with type 2 diabetes.²⁵Afzal S, Brøndum-Jacobsen P, Bojesen SE, Nordestgaard BG. Vitamin D concentration, obesity, and risk of diabetes: a Mendelian randomisation study. Lancet Diabetes and Endocrinology. 2014 Apr;2(4):298-306. 
• Compared with the controls (noncancer patients), heterozygote and dominant models with the VDR rs1544410 (BsmI) is likely the best genetic model for detecting the risk of ovarian cancer in Caucasian patients.²⁶Li J, Li B et al. Do genetic polymorphisms of the vitamin D receptor contribute to breast/ovarian cancer? A systematic review and network meta-analysis. Gene. 2018 Nov 30;677:211-227.
• Vitamin D and its receptor VDR contribute to the protective process of probiotics.²⁷Shang M, Sun J. Vitamin D/VDR, probiotics, and gastrointestinal diseases. Current Medicinal Chemistry. 2017;24(9):876-887.
• The association between insulin resistance-related diseases and VDR ApaI, BsmI, FokI variant was more obvious in dark-pigmented Caucasians and Asians but not in Caucasians with white skin.²⁸Han FF, Lv Y et al. VDR gene variation and insulin resistance related diseases. Lipids in Health and Disease. 2017 Aug 19;16(1):157.

Preclinical evidence 

Notable preclinical evidence; clinical evidence is listed in How can vitamin D help you? What the research says ›

Improving treatment outcomes

• Vitamin D enhanced antitumor activity of docetaxel in an androgen-independent prostate cancer cell line in a preclinical study.²⁹Ting HJ, Hsu J, Bao BY et al. Docetaxel-induced growth inhibition and apoptosis in androgen independent prostate cancer cells are enhanced by 1alpha, 25- dihydroxyvitamin D3. Cancer Letters. 2007;247:122–9.
• Calcitriol enhanced activity of docetaxel, paclitaxel, and platinum compounds in preclinical studies of prostate cancer.³⁰Beer TM, Hough KM et al. Weekly high dose calcitriol and docetaxel in advanced prostate cancer. Seminars in Oncology. 2001;28(4 Suppl 15):49–55. 
• Vitamin D₃ with or without docetaxel was similarly effective in reducing CD34(+) cell levels within the spleen, lymph nodes, and tumor.³¹Young MR, Lathers DM. Combination docetaxel plus vitamin D(3) as an immune therapy in animals bearing squamous cell carcinomas. Otolaryngology—Head and Neck Surgery. 2005;133:611–8. 
• Vitamin D signaling inhibits the expression of the tumor progression gene Id1, reducing breast cancer metastasis in preclinical studies.³²Williams JD, Aggarwal A et al. Tumor autonomous effects of vitamin D deficiency promote breast cancer metastasis. Endocrinology. 2016 Apr;157(4):1341-7.

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