Abstract
Previous prospective studies have shown inconsistent associations between serum 25-hydroxyvitamin D [25(OH)D] level and lung cancer incidence. The aim of the present study was to explore the associations of serum 25(OH)D levels with incidence of lung cancer overall and different histologic types. We performed a population-based prospective case-cohort study including 696 incident lung cancer cases and 5804 individuals in a subcohort who participated in the second survey of the Nord-Trøndelag Health Study in Norway. Cox proportional hazards regression models counting for the case-cohort design were used to estimate hazard ratios (HRs) with 95% confidence interval (CIs) for lung cancer overall or histologic types in relation to serum 25(OH)D levels. Compared with the fourth season-specific quartile of 25(OH)D (median 68.0 nmol/L), lower 25(OH)D levels were not associated with the incidence of overall, small or squamous cell lung cancer. However, the risk of adenocarcinoma was lower in the second and third quartiles (median 39.9 and 51.5 nmol/L) compared with the fourth quartile, with HRs of 0.63 (95% CI 0.41–0.98) and 0.58 (0.38–0.88), respectively. The associations of lower levels of 25(OH)D with a reduced risk of adenocarcinoma were only observed in the overweight/obese subjects [HRs for second and third quartiles: 0.40 (0.22–0.72) and 0.50 (0.27–0.92)] but not in the normal weight subjects [HRs: 0.95 (0.52–1.75) and 0.60 (0.32–1.10)]. Serum 25(OH)D levels were not associated with the risk of lung cancer in general. The observation that lower 25(OH)D levels were associated with a lower risk of adenocarcinoma should be interpreted with caution.

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References
GLOBOCAN 2012, Estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer. 2016. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.
Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004.
Lee PN, Forey BA, Coombs KJ. Systematic review with meta-analysis of the epidemiological evidence in the 1900s relating smoking to lung cancer. BMC Cancer. 2012;12:385. doi:10.1186/1471-2407-12-385.
Lewis DR, Check DP, Caporaso NE, Travis WD, Devesa SS. US lung cancer trends by histologic type. Cancer. 2014;120(18):2883–92. doi:10.1002/cncr.28749.
Cheng TY, Cramb SM, Baade PD, Youlden DR, Nwogu C, Reid ME. The international epidemiology of lung cancer: latest trends, disparities, and tumor characteristics. J Thorac Oncol. 2016;11(10):1653–71. doi:10.1016/j.jtho.2016.05.021.
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.
Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014;14(5):342–57. doi:10.1038/nrc3691.
Arabi A, El Rassi R, El-Hajj FG. Hypovitaminosis D in developing countries-prevalence, risk factors and outcomes. Nat Rev Endocrinol. 2010;6(10):550–61. doi:10.1038/nrendo.2010.146.
Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol. 2014;144(Pt A):138–45. doi:10.1016/j.jsbmb.2013.11.003.
Sun YQ, Langhammer A, Skorpen F, Chen Y, Mai XM. Serum 25-hydroxyvitamin D level, chronic diseases and all-cause mortality in a population-based prospective cohort: the HUNT Study, Norway. BMJ Open. 2017;7(6):e017256. doi:10.1136/bmjopen-2017-017256.
Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ (Clin Res Ed). 2014;348:g1903. doi:10.1136/bmj.g1903.
Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst. 2006;98(7):451–9. doi:10.1093/jnci/djj101.
Kilkkinen A, Knekt P, Heliovaara M, et al. Vitamin D status and the risk of lung cancer: a cohort study in Finland. Cancer Epidemiol Biomarkers Prev. 2008;17(11):3274–8. doi:10.1158/1055-9965.EPI-08-0199.
Ordonez-Mena JM, Schottker B, Fedirko V, et al. Pre-diagnostic vitamin D concentrations and cancer risks in older individuals: an analysis of cohorts participating in the CHANCES consortium. Eur J Epidemiol. 2016;31(3):311–23. doi:10.1007/s10654-015-0040-7.
Ordonez-Mena JM, Schottker B, Haug U, et al. Serum 25-hydroxyvitamin d and cancer risk in older adults: results from a large German prospective cohort study. Cancer Epidemiol Biomarkers Prev. 2013;22(5):905–16. doi:10.1158/1055-9965.EPI-12-1332.
Skaaby T, Husemoen LL, Thuesen BH, et al. Prospective population-based study of the association between serum 25-hydroxyvitamin-D levels and the incidence of specific types of cancer. Cancer Epidemiol Biomarkers Prev. 2014;23(7):1220–9. doi:10.1158/1055-9965.EPI-14-0007.
Weinstein SJ, Yu K, Horst RL, Parisi D, Virtamo J, Albanes D. Serum 25-hydroxyvitamin D and risk of lung cancer in male smokers: a nested case-control study. PLoS ONE. 2011;6(6):e20796. doi:10.1371/journal.pone.0020796.
Wong YY, Hyde Z, McCaul KA, et al. In older men, lower plasma 25-hydroxyvitamin D is associated with reduced incidence of prostate, but not colorectal or lung cancer. PLoS ONE. 2014;9(6):e99954. doi:10.1371/journal.pone.0099954.
Afzal S, Bojesen SE, Nordestgaard BG. Low plasma 25-hydroxyvitamin D and risk of tobacco-related cancer. Clin Chem. 2013;59(5):771–80. doi:10.1373/clinchem.2012.201939.
Krokstad S, Langhammer A, Hveem K, et al. Cohort Profile: the HUNT Study, Norway. Int J Epidemiol. 2013;42(4):968–77. doi:10.1093/ije/dys095.
Cancer Registry of Norway. 2017. https://www.kreftregisteret.no/.
Cancer Registry of Norway. Cancer in Norway 2014—Cancer incidence, mortality, survival and prevalence in Norway. Oslo: Cancer Registry of Norway; 2015.
International classification of diseases for oncology (ICD-O). 3rd ed. World Health Organization; 2013.
Barlow WE, Ichikawa L, Rosner D, Izumi S. Analysis of case-cohort designs. J Clin Epidemiol. 1999;52(12):1165–72.
Coviello M. Ordinary case–cohort design and analysis. Stata Technical Bulletin STB-59. 2001.
Wagner D, Hanwell HE, Vieth R. An evaluation of automated methods for measurement of serum 25-hydroxyvitamin D. Clin Biochem. 2009;42(15):1549–56. doi:10.1016/j.clinbiochem.2009.07.013.
Wang Y, Jacobs EJ, McCullough ML, et al. Comparing methods for accounting for seasonal variability in a biomarker when only a single sample is available: insights from simulations based on serum 25-hydroxyvitamin d. Am J Epidemiol. 2009;170(1):88–94. doi:10.1093/aje/kwp086.
Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Dietary reference intakes for calcium and vitamin D. Washington: The National Academies Press; 2011.
Jacobs ET, Kohler LN, Kunihiro AG, Jurutka PW. Vitamin D and colorectal, breast, and prostate cancers: a review of the epidemiological evidence. J Cancer. 2016;7(3):232–40. doi:10.7150/jca.13403.
Meyer HE, Robsahm TE, Bjorge T, Brustad M, Blomhoff R. Vitamin D, season, and risk of prostate cancer: a nested case-control study within Norwegian health studies. Am J Clin Nutr. 2013;97(1):147–54. doi:10.3945/ajcn.112.039222.
Larsen IK, Smastuen M, Johannesen TB, et al. Data quality at the Cancer Registry of Norway: an overview of comparability, completeness, validity and timeliness. Eur J Cancer. 2009;45(7):1218–31. doi:10.1016/j.ejca.2008.10.037.
Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–81. doi:10.1056/NEJMra070553.
Langhammer A, Krokstad S, Romundstad P, Heggland J, Holmen J. The HUNT study: participation is associated with survival and depends on socioeconomic status, diseases and symptoms. BMC Med Res Methodol. 2012;12:143. doi:10.1186/1471-2288-12-143.
Jorde R, Sneve M, Hutchinson M, Emaus N, Figenschau Y, Grimnes G. Tracking of serum 25-hydroxyvitamin D levels during 14 years in a population-based study and during 12 months in an intervention study. Am J Epidemiol. 2010;171(8):903–8. doi:10.1093/aje/kwq005.
Schottker B, Haug U, Schomburg L, et al. Strong associations of 25-hydroxyvitamin D concentrations with all-cause, cardiovascular, cancer, and respiratory disease mortality in a large cohort study. Am J Clin Nutr. 2013;97(4):782–93. doi:10.3945/ajcn.112.047712.
Gaksch M, Jorde R, Grimnes G, et al. Vitamin D and mortality: individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium. PLoS ONE. 2017;12(2):e0170791. doi:10.1371/journal.pone.0170791.
Schottker B, Jansen EH, Haug U, Schomburg L, Kohrle J, Brenner H. Standardization of misleading immunoassay based 25-hydroxyvitamin D levels with liquid chromatography tandem-mass spectrometry in a large cohort study. PLoS ONE. 2012;7(11):e48774. doi:10.1371/journal.pone.0048774.
Duan P, Hu C, Quan C, et al. Body mass index and risk of lung cancer: systematic review and dose-response meta-analysis. Sci Rep. 2015;5:16938. doi:10.1038/srep16938.
Yang Y, Dong J, Sun K, et al. Obesity and incidence of lung cancer: a meta-analysis. Int J Cancer. 2013;132(5):1162–9. doi:10.1002/ijc.27719.
Carreras-Torres R, Haycock PC, Relton CL, et al. The causal relevance of body mass index in different histological types of lung cancer: a Mendelian randomization study. Sci Rep. 2016;6:31121. doi:10.1038/srep31121.
Vimaleswaran KS, Berry DJ, Lu C, et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013;10(2):e1001383. doi:10.1371/journal.pmed.1001383.
Vieira AR, Abar L, Vingeliene S, et al. Fruits, vegetables and lung cancer risk: a systematic review and meta-analysis. Ann Oncol. 2016;27(1):81–96. doi:10.1093/annonc/mdv381.
Yu N, Su X, Wang Z, Dai B, Kang J. Association of dietary vitamin A and beta-carotene intake with the risk of lung cancer: a meta-analysis of 19 publications. Nutrients. 2015;7(11):9309–24. doi:10.3390/nu7115463.
Chen G, Kim SH, King AN, et al. CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma. Clin Cancer Res. 2011;17(4):817–26. doi:10.1158/1078-0432.ccr-10-1789.
Acknowledgements
The Nord-Trøndelag Health Study (HUNT) is a collaboration between the HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), the Nord-Trøndelag County Council, and the Norwegian Institute of Public Health. The authors especially thank the HUNT Research Centre laboratory personnel for the measurement of serum 25(OH)D levels. We are also grateful to Professor Margaret May at University of Bristol for statistical consultation.
Funding
This work was supported by The Norwegian Cancer Society (project ID 5769155-2015) and The Research Council of Norway “Gaveforsterkning”.
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YQS, AL, YC and XMM contributed to the study design. XMM and AL contributed to data collection. CW contributed to statistical analyses. YQS conducted statistical analyses, interpreted results and wrote the initial draft of the manuscript. AL, CW, FS, YC, TILN, PRR and XMM participated in the data interpretation and helped to write the final draft of the manuscript.
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YQS reports grants from The Norwegian Cancer Society during the conduct of the study. All other authors declare that they have no conflict of interest.
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Disclaimer: The study has used data from the Cancer Registry of Norway. The interpretation and reporting of these data are the sole responsibility of the authors, and no endorsement by the Cancer Registry of Norway is intended nor should be inferred.
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Sun, YQ., Langhammer, A., Wu, C. et al. Associations of serum 25-hydroxyvitamin D level with incidence of lung cancer and histologic types in Norwegian adults: a case-cohort analysis of the HUNT study. Eur J Epidemiol 33, 67–77 (2018). https://doi.org/10.1007/s10654-017-0324-1
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DOI: https://doi.org/10.1007/s10654-017-0324-1