VITAMIN D RECEPTOR POLYMORPHISMS AND LUNG CANCER: BIOLOGICAL RATIONALE, EPIDEMIOLOGICAL SIGNALS, AND TRANSLATIONAL IMPLICATIONS – A NARRATIVE REVIEW

GOGINENI RAJYALAKSHMI; MUNIINATHAN NATARAJAN; GIRIJA MENON M; SURESH ARUMUGAM A; KUPPUSAMY BASKARAN

doi:10.22159/ajpcr.2025v18i10.56773

Authors

GOGINENI RAJYALAKSHMI Department of Biochemistry, Meenakshi Medical College Hospital and Research Institute, Meenakshi Academy of Higher Education and Research, Kanchipuram, Tamil Nadu, India.
MUNIINATHAN NATARAJAN Central Research Laboratory, Meenakshi Medical College Hospital and Research Institute, Meenakshi Academy of Higher Education and Research, Kanchipuram, Tamil Nadu, India.
GIRIJA MENON M Department of Biochemistry, RVM Institute of Medical Science and Research Centre, Siddipet, Telangana, India.
SURESH ARUMUGAM A Central Research Laboratory, Meenakshi Medical College Hospital and Research Institute, Meenakshi Academy of Higher Education and Research, Kanchipuram, Tamil Nadu, India
KUPPUSAMY BASKARAN Central Research Laboratory, Meenakshi Medical College Hospital and Research Institute, Meenakshi Academy of Higher Education and Research, Kanchipuram, Tamil Nadu, India.

DOI:

https://doi.org/10.22159/ajpcr.2025v18i10.56773

Keywords:

Vitamin D receptor (VDR), polymorphism, lung cancer, non-small-cell lung cancer (NSCLC), genetic susceptibility, translational implications

Abstract

This narrative review integrates mechanistic biology with population evidence to appraise when and why vitamin-D receptor (VDR) polymorphisms associate with lung cancer risk and outcomes. Using a systematic approach to searching, screening, and extraction across major databases, we included human observational studies (case-control/cohort), pooled analyses, and lung-specific functional experiments, focusing on incidence/risk, stage, overall/progression-free survival, and effect modification by smoking and vitamin-D axis status. A coherent, context-dependent signal emerges: TaqI (rs731236) shows the most reproducible susceptibility association, stronger in Asian ancestry, smokers, and non-small-cell lung cancer, while BsmI (rs1544410) and, in some settings, ApaI (rs7975232) tend to be protective; FokI (rs2228570) contributes to risk in certain populations and carries a pathway-level survival signal. Lung-specific evidence that ligand-activated VDR represses histidine-rich calcium-binding protein (HRC), curbing proliferation, migration, and xenograft growth, provides a credible mechanistic bridge from genotype to phenotype. However, heterogeneity in genotyping platforms and quality control, incomplete Hardy–Weinberg reporting, small or imbalanced cohorts, variable adjustment (smoking intensity, histology, stage), and sparse contemporaneous 25(OH)D and environmental data limit causal inference and impede quantitative synthesis in survival analyses. Taken together, current data support cautious, genotype-aware research use of the vitamin-D axis rather than routine clinical testing. Priority next steps include adequately powered, multi-ancestry cohorts with harmonised genotyping and prespecified covariates, standardised rsID-anchored genetic models, integrated vitamin-D/environmental measures, pathway-wide analyses across VDR–CYP27B1–CYP24A1–CYP2R1–GC, and prospective validation of genotype-augmented risk scores and NSCLC prognostic tools to test true translational utility.

Downloads

Download data is not yet available.

References

1. Li C, Lei S, Ding L, Xu Y, Wu X, Wang H, et al. Global burden and trends of lung cancer incidence and mortality. Chin Med J (Engl). 2023 Jul 5;136(13):1583-90. doi: 10.1097/CM9.0000000000002529. PMID: 37027426

2. Cheng ES, Weber M, Steinberg J, Yu XQ. Lung cancer risk in never-smokers: An overview of environmental and genetic factors. Chin J Cancer Res. 2021;33(5):548-62. doi: 10.21147/j.issn.1000- 9604.2021.05.02, PMID 34815629

3. Jovičić-Bata J, Sazdanić-Velikić D, Ševo M, Milanović M, Tubić T, Bijelović M, et al. Lifestyle, environmental, occupational, and dietary risk factors in small-cell vs. Non-small-cell advanced lung cancer patients: Is there a connection? Cancers (Basel). 2025 Mar 3;17(5):864. doi: 10.3390/cancers17050864. PMID: 40075710

4. Agonsanou H, Figueiredo R, Bergeron M. Risk factors for the development of lung cancer around the world: A review. Explor Med. 2023;4(6):1168-88. doi: 10.37349/emed.2023.00201

5. Elsalahaty MI, Alkafaas SS, Bashir AO, El-Tarabily KA, El-Saadony MT, Yousef EH. Revealing the association between vitamin D metabolic pathway gene variants and lung cancer risk: A systematic review and meta-analysis. Front Genet. 2024 Feb 28;15:1302527. doi: 10.3389/fgene.2024.1302527. PMID: 38482381

6. Cheng TY, Goodman GE, Thornquist MD, Barnett MJ, Beresford SA, LaCroix AZ, et al. Estimated intake of vitamin D and its interaction with vitamin A on lung cancer risk among smokers. Int J Cancer. 2014 Nov 1;135(9):2135-45. doi: 10.1002/ijc.28846. PMID: 24622914

7. Cheng TY, Song X, Beresford SA, Ho GY, Johnson KC, Datta M, et al. Serum 25-hydroxyvitamin D concentrations and lung cancer risk in never-smoking postmenopausal women. Cancer Causes Control. 2017;28(10):1053-63. doi: 10.1007/s10552-017-0956-1. PMID: 28900765

8. Fekete M, Lehoczki A, Szappanos Á, Zábó V, Kaposvári C, Horváth A, et al. Vitamin D and colorectal cancer prevention: Immunological mechanisms, inflammatory pathways, and nutritional implications. Nutrients. 2025;17(8):1351. doi: 10.3390/nu17081351. PMID: 40284214

9. El-Sharkawy A, Malki A. Vitamin D signaling in inflammation and cancer: Molecular mechanisms and therapeutic implications. Molecules. 2020;25(14):3219. doi: 10.3390/molecules25143219. PMID: 32679655

10. Dallavalasa S, Tulimilli SV, Bettada VG, Karnik M, Uthaiah CA, Anantharaju PG, et al. Vitamin D in cancer prevention and treatment: A review of epidemiological, preclinical, and cellular studies. Cancers (Basel). 2024 Sep 20;16(18):3211. doi: 10.3390/cancers16183211. PMID: 39335182

11. Wu X, Hu W, Lu L, Zhao Y, Zhou Y, Xiao Z, et al. Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment. Acta Pharm Sin B. 2019 Mar;9(2):203-219. doi: 10.1016/j.apsb.2018.09.002. PMID: 30972274

12. Chandler PD, Chen WY, Ajala ON, Hazra A, Cook N, Bubes V, et al. Effect of vitamin D3 supplements on development of advanced cancer: A secondary analysis of the VITAL randomized clinical trial. JAMA Netw Open. 2020 Nov 2;3(11):e2025850. doi: 10.1001/jamanetworkopen.2020.25850. Erratum in: JAMA Netw Open. 2020 Dec 1;3(12):e2032460. doi: 10.1001/ jamanetworkopen.2020.32460. PMID: 33206192

13. Zhang R, Zhang Y, Liu Z, Pei Y, Xu P, Chong W, et al. Association between vitamin D supplementation and cancer mortality: Asystematic review and meta-analysis. Cancers (Basel). 2022;14(15):3717. doi: 10.3390/cancers14153717, PMID 35954381

14. Lawler T, Warren Andersen S. Serum 25-hydroxyvitamin D and cancer risk: A systematic review of Mendelian randomization studies. Nutrients. 2023;15(2):422. doi: 10.3390/nu15020422, PMID 36678292

15. Ciocarlie T, Motofelea AC, Motofelea N, Dutu AG, Crăciun A, Costachescu D, et al. Exploring the role of vitamin D, vitamin D-dependent proteins, and vitamin D receptor gene variation in lung cancer risk. Int J Mol Sci. 2024;25(12):6664. doi: 10.3390/ ijms25126664, PMID 38928369

16. Kilkkinen A, Knekt P, Heliövaara M, Rissanen H, Marniemi J, Hakulinen T, et al. Vitamin D status and the risk of lung cancer: A cohort studyinFinland.CancerEpidemiolBiomarkersPrev.2008;17(11):3274-8. doi: 10.1158/1055-9965.EPI-08-0199, PMID 18990771

17. Vaughan-Shaw PG, O’Sullivan F, Farrington SM, Theodoratou E, Campbell H, Dunlop MG, et al. The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: Systematic review and meta-analysis. Br J Cancer. 2017;116(8):1092-110. doi: 10.1038/bjc.2017.44, PMID 28301870

18. Gasperini B, Visconti VV, Ciccacci C, Falvino A, Gasbarra E, Iundusi R, et al. Role of the vitamin D receptor (VDR) in the pathogenesis of osteoporosis: A genetic, epigenetic and molecular pilot study. Genes (Basel). 2023 Feb 21;14(3):542. doi: 10.3390/ genes14030542. PMID: 36980815

19. Meyer V, Bornman L. Cdx-2 polymorphism in the vitamin D receptor gene (VDR) marks VDR expression in monocyte/macrophages through VDR promoter methylation. Immunogenetics. 2018;70(8):523-32. doi: 10.1007/s00251-018-1063-5, PMID 29808256

20. Trefilio LM, Bottino L, de Carvalho Cardoso R, Montes GC, Fontes-Dantas FL. The impact of genetic variants related to vitamin D and autoimmunity: A systematic review. Heliyon. 2024 Mar 21;10(7):e27700. doi: 10.1016/j.heliyon.2024.e27700. PMID: 38689997; PMC11059421.

21. Xiong L, Cheng J, Gao J, Wang J, Liu X, Wang L. Vitamin D receptor genetic variants are associated with chemotherapy response and prognosis in patients with advanced non-small-cell lung cancer. Clin Lung Cancer. 2013;14(4):433-9. doi: 10.1016/j.cllc.2013.01.004, PMID 23522953

22. Yang J, Fang M, Hou M, Duan Y, Wang J, Hu K, et al. VDR decrease enhances the efficacy of 1,25-dihydroxyvitamin D3 inhibiting gefitinib resistance by regulating EGFR/FASN loop in NSCLC cells. Pharmaceuticals (Basel). 2025 Aug 21;18(8):1238. doi: 10.3390/ ph18081238. PMID: 40872626

23. Duan GQ, Zheng X, Li WK, Zhang W, Li Z, Tan W. The association between VDR and GC polymorphisms and lung cancer risk: A systematic review and meta-analysis. Genet Test Mol Biomarkers. 2020;24(5):285-95. doi: 10.1089/gtmb.2019.0187, PMID 32255717

24. Li M, Liu X, Liu N, Yang T, Shi P, He R, et al. Association between polymorphisms of vitamin D receptor and lung cancer susceptibility: Evidence from an updated meta-analysis. JCancer. 2019;10(16):3639-49. doi: 10.7150/jca.33431, PMID 31333781

25. Jianhai T, Jian L, Long Z, Wei W, Shumao Z, Yiming W, et al. Vitamin D receptor gene polymorphisms and its interactions with environmental factors on renal cell carcinoma risk. Genes Environ. 2021;43(1):19. doi: 10.1186/s41021-021-00185-3, PMID 34006324

26. Debata T, Swain A, Jena SR, Das SN, Mishra N, Samanta L. Vitamin D receptor gene polymorphism in oral cancer as a function of tobacco consumption: An evidence based systematic review and meta-analysis. Front Oral Health. 2025 Apr 28;6:1550683. doi: 10.3389/ froh.2025.1550683. PMID: 40356850

27. Serrano D, Gnagnarella P, Raimondi S, Gandini S. Meta-analysis on vitamin D receptor and cancer risk: Focus on the role of TaqI, ApaI, and Cdx2 polymorphisms. Eur J Cancer Prev. 2016;25(1):85-96. doi: 10.1097/CEJ.0000000000000132. PMID: 25738688

28. Yadav U, Kumar P, Rai V. Vitamin D receptor (VDR) gene FokI, BsmI, ApaI, and TaqI polymorphisms and osteoporosis risk: A meta-analysis. Egypt J Med Hum Genet. 2020;21(1):15. doi: 10.1186/s43042-020- 00057-5

29. Thorne J, Campbell MJ. The vitamin D receptor in cancer: Symposium on “Diet and cancer”. Proc Nutr Soc. 2008;67(2):115-27. doi: 10.1017/ S0029665108006964, PMID 18412986

30. Carlberg C, Muñoz A. An update on vitamin D signaling and cancer. Semin Cancer Biol. 2022;79:217-30. doi: 10.1016/j. semcancer.2020.05.018, PMID 32485310

31. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014;21(3):319-29. doi: 10.1016/j. chembiol.2013.12.016. PMID: 24529992

32. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5(10):3993-4021. doi: 10.3390/nu5103993. PMID: 24084056

33. Voltan G, Cannito M, Ferrarese M, Ceccato F, Camozzi V. Vitamin D: An overview of gene regulation, ranging from metabolism to genomic effects. Genes (Basel). 2023;14(9):1691. doi: 10.3390/genes14091691. PMID: 37761831

34. Liebermann DA, Hoffman B. Gadd45 in stress signaling. J Mol Signal. 2008;3:15. doi: 10.1186/1750-2187-3-15. PMID: 18789159

35. Abbas T, Dutta A. p21 in cancer: Intricate networks and multiple activities. Nat Rev Cancer. 2009;9(6):400-14. doi: 10.1038/nrc2657. PMID: 19440234

36. Stojanovic B, Jovanovic I, Dimitrijevic Stojanovic M, Stojanovic BS, Kovacevic V, Radosavljevic I, et al. Oxidative stress-driven cellular senescence: Mechanistic crosstalk and therapeutic horizons. Antioxidants (Basel). 2025;14(8):987. doi: 10.3390/antiox14080987. PMID: 4086788

37. Hoseinkhani Z, Rastegari-Pouyani M, Tajemiri F, Yari K, Mansouri K. Association of vitamin D receptor polymorphisms (FokI (rs2228570), ApaI (rs7975232), BsmI (rs1544410), and TaqI (rs731236)) with gastric cancer in a Kurdish population from west of Iran. Rep Biochem Mol Biol. 2021;9(4):435-41. doi: 10.52547/rbmb.9.4.435. PMID: 33969137

38. Agliardi C, Guerini FR, Zanzottera M, Bolognesi E, Meloni M, Riboldazzi G, et al. The VDR FokI (rs2228570) polymorphism is involved in Parkinson’s disease. J Neurol Sci. 2021;428:117606. doi: 10.1016/j.jns.2021.117606. PMID: 34365149

39. González Rojo P, Pérez Ramírez C, Gálvez Navas JM, Pineda Lancheros LE, Rojo Tolosa S, Ramírez Tortosa MC, et al. Vitamin D-related single nucleotide polymorphisms as risk biomarker of cardiovascular disease. Int J Mol Sci. 2022;23(15):8686. doi: 10.3390/ijms23158686. PMID: 35955825

40. Liu N, Li X, Fu Y, Li Y, Lu W, Pan Y, et al. Inhibition of lung cancer by vitamin D depends on downregulation of histidine-rich calcium-binding protein. J Adv Res. 2021;29:13-22. doi: 10.1016/j.jare.2020.08.013. PMC8020154

41. Gromowski T, Gapska P, Scott RJ, Kąklewski K, Marciniak W, Durda K, et al. Serum 25(OH)D concentration, common variants of the VDR gene and lung cancer occurrence. Int J Cancer. 2017;141(2):336-41. doi: 10.1002/ijc.30740, PMID 28411367

42. Larysz D, Recław R, Suchanecka A, Dziurawiec W, Tkacz R, Strońska- Pluta A, et al. Vitamin D genetics beyond serum 25(OH)D: VDR rs2228570 (FokI) polymorphism, inflammation, and quality of life in orthopedic patients. Nutrients. 2025;17(18):2926. doi: 10.3390/ nu17182926. PMID: 41010452

43. Turna A, Pekcolaklar A, Metin M, Yaylim I, Gurses A. The effect of season of operation on the survival of patients with resected non-small cell lung cancer. Interact Cardiovasc Thorac Surg. 2012;14(2):151-5. doi: 10.1093/icvts/ivr063. PMID: 22159250

44. Lei W, Tian H, Xia Y. Association between the TaqI (rs731236 T>C) gene polymorphism and dental caries risk: A meta-analysis. Genet Test Mol Biomarkers. 2021;25(5):368-75. doi: 10.1089/gtmb.2020.0263.

45. Araz M. Does vitamin D replacement alter the chemotherapy outcome in lung cancer. EJMO. 2019;3:112-5. doi: 10.14744/ejmo.2019.31913

46. Ottaiano A, Facchini BA, Iacovino M, Santorsola M, Facchini S, Di Mauro G, et al. Impact of vitamin D levels on progression-free survival and response to neoadjuvant chemotherapy in breast cancer patients: A systematic review and meta-analysis. Cancers (Basel). 2024;16(24):4206. doi: 10.3390/cancers16244206. PMID: 39766105

47. Li R, Tian M, Ma M, Pei J, Song Y, Han B. Five vitamin D receptor polymorphisms (FokI, BsmI, Apa1, Taq1, and Cdx2) and lung cancer risk. J Clin Oncol. 2012;30(15_suppl):e12013. doi: 10.1200/ jco.2012.30.15_suppl.e12013

48. Pineda-Lancheros LE, Gálvez-Navas JM, Rojo-Tolosa S, Membrive- Jiménez C, Valverde-Merino MI, Martínez-Martínez F, et al. Polymorphisms in VDR, CYP27B1, CYP2R1, GC and CYP24A1 genes as biomarkers of survival in non-small cell lung cancer: A systematic review. Nutrients. 2023;15(6):1525. doi: 10.3390/nu15061525. PMID: 36986255

49. Xu Y, He B, Pan Y, Deng Q, Sun H, Li R, et al. Systematic review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Tumour Biol. 2014;35(5):4153-69. doi: 10.1007/s13277-013-1544-y. PMID: 24408013

50. Tuncel G, Temel SG, Ergoren MC. Strong association between VDR FokI (rs2228570) gene variant and serum vitamin D levels in Turkish Cypriots. Mol Biol Rep. 2019;46(3):3349-55. doi: 10.1007/s11033- 019-04796-6. PMID: 30977086

51. Laczmanski L, Laczmanska I, Lwow F. Association of select vitamin D receptor gene polymorphisms with the risk of tobacco-related cancers - a meta-analysis. Sci Rep. 2019;9:16026. doi: 10.1038/ s41598-019-52519-5. PMID: 31690771