Supplementary Table 1. Studies investigating blood 25(OH)D in relation to lung cancer incidence or mortality

Study, Country (First author) / Design / Number of cases / Risk estimates (95% CI) / Smoking status
Mini-Finland Health Survey, Finland (Kilkkinen)[1] / Cohort / M 97 cases / ≥52 vs ≤34 nmol/L, RR=1.03 (0.59-1.82) / 58% smokers
F 25 cases / ≥47 vs. ≤30 nmol/L, RR=0.16 (0.04-0.59) / 19% smokers
NHANES III, US (Freedman)[2] / Cohort / M 165 deaths / ≥100 vs. <50 nmol/L, RR=1.87 (1.04-3.34)1 / 25% current smokers (M+F)
F 87 deaths / ≥80 vs. <50 nmol/L, RR=0.64 (0.23-1.79)
NHANES III, US (Cheng)[3] / Cohort / M+F 258 deaths / Q4 (>80 nmol/L) vs. Q1 (<44 nmol/L), HR=0.95 (0.62-1.44) / 25% current smokers
M+F 51 deaths / Q4 vs. Q1, HR=0.31 (0.13-0.76) / Never smokers + former smokers quitting ≥20 y
Health Professionals Follow-Up Study, US (Giovannucci)[4] / Cohort / M 418 cases / An increment
of 25 nmol/L in predicted 25(OH)D, RR=0.8 (0.6-1.2) / 10% current smokers
Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, Finland (Weinstein)[5] / Nested case-control / M 500 cases / Season standardized Q5 vs. Q1, OR=0.83 (0.53-1.31); a 10 nmol/L increase in
25(OH)D in the darker season, OR=0.89 (0.81-0.98) / All current smokers
Denmark (Skaaby)[6] / Cohort / M+F 110 cases / Q4 vs. Q1, HR=0.91 (0.51-1.62) / 37% current smokers
ESTHER, Germany (Ordonez-Mena)[7, 8] / Cohort / M+F 136 cases / >50 vs. <30 nmol/L, RR=0.86 (0.52-1.45)[9] / 15% current smokers
TROMSØ,Norway (Ordonez-Mena)[8] / Cohort / M+F 58 cases / >50 vs. <30 nmol/L, RR=0.45 (0.17-1.20)[9] / Former and never smokers only
Copenhagen City Heart Study, Denmark (Afzal)[10] / Cohort / M+F 507 cases / A 50% reduction in plasma 25(OH)D, HR=1.19 (1.09-1.31) / 80% ever smokers
HR=1.20 (1.13-1.28) / Ever smokers
HR=1.05 (0.81-1.38) / Never smokers
Health in Men Study, Australia (Wong)[11] / Cohort / M 93 cases / >75 vs. 50-75 nmol/L, HR=1.37 (0.85-2.21) / 15% current smokers

Supplementary Table 2. The number and percentage of lung cancer cases according to tumor histology and stage

Tumor histology1 (%)
Adenocarcinoma / 170 (57.1%)
Squamous cell carcinoma / 12 (4.0%)
Large cell carcinoma and other NSCLC / 9 (3.0%)
Small cell lung cancer / 6 (2.0%)
Others / 69 (23.2%)
Unknown / 32 (10.7%)
Tumor stage2 (%)
Localized / 84 (28.2)
Regional / 56 (18.8)
Distant / 96 (32.2)
Unknown / 62 (20.8)

1Histology subtypes were classified based on the WHO classification of Tumors for tumors of the lung: adenocarcinoma (ICD-O-2 site code=8140, 8250, 8260, 8480, 8481, 8550); squamous cell carcinoma (8052, 8070, 8071); large cell carcinoma and other NSCLC (8012, 8032, 8560, 8980); small cell lung cancer (8041); Others (8000 [neoplasm], 8010 [carcinoma, NOS], 8240 [carcinoid], 8246 [neuroendocrine carcinoma], 8323 [mixed cell adenoma]).

2 The Surveillance, Epidemiology, and End Results Program (SEER) staging

Supplementary Table 3. Pearson correlation coefficients (r) between baseline serum vitamin concentrations and estimated intake levels

Estimated intake levels
Vitamin D (IU/d) / Vitamin A (RAE/d)2 / Retinol (µg/d)
Serum concentrations / Total1 / Diet / Supplements / Total / Diet / Supplements / Total / Diet / Supplements
25(OH)D (mmol/L) / 0.343 / 0.13 / 0.32 / 0.22 / 0.14 / 0.19 / 0.19 / 0.09 / 0.18
Retinol (µg/dL) / 0.21 / 0.03 / 0.22 / 0.08 / 0.07 / 0.07 / 0.05 / 0.002 / 0.05
Retinyl palmitate (µg/dL) / 0.22 / 0.004 / 0.25 / 0.34 / 0.07 / 0.34 / 0.38 / –0.01 / 0.39

1 Total intake = dietary intake + supplemental intake

2 RAE, retinol activity equivalent; the values include retinol and carotenoids

3 r = 0.43 among women who had blood draw in winter; r = 0.28 among women who had blood draw in summer (both p<0.001)

References

1.Kilkkinen A, Knekt P, Heliövaara M, et al. (2008) Vitamin D status and the risk of lung cancer: a cohort study in Finland. Cancer Epidemiol Biomarkers Prev. 17: 3274-8.

2.Freedman DM, Looker AC, Abnet CC, Linet MS, Graubard BI. (2010) Serum Vitamin D and Cancer Mortality in the NHANES III Study (1988-2006). Cancer Res. 70: 8587-97.

3.Cheng TY, Neuhouser ML. (2012) Serum 25-hydroxyvitamin D, interaction with vitamin A and lung cancer mortality in the U.S. population. Cancer Causes Control. 23: 1557-65.

4.Giovannucci E, Liu Y, Rimm EB, et al. (2006) Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. Journal of the National Cancer Institute. 98: 451-9.

5.Weinstein SJ, Yu K, Horst RL, Parisi D, Virtamo J, Albanes D. (2011) Serum 25-hydroxyvitamin d and risk of lung cancer in male smokers: a nested case-control study. PLoS One. 6: e20796.

6.Skaaby T, Husemoen LL, Thuesen BH, et al. (2014) 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. 23: 1220-9.

7.Ordonez-Mena JM, Schottker B, Haug U, et al. (2013) Serum 25-hydroxyvitamin d and cancer risk in older adults: results from a large German prospective cohort study. Cancer Epidemiol Biomarkers Prev. 22: 905-16.

8.Ordonez-Mena JM, Schottker B, Fedirko V, et al. (2015. doi:10.​1007/​s10654-015-0040-7 [Epub ahead of print]) Pre-diagnostic vitamin D concentrations and cancer risks in older individuals: an analysis of cohorts participating in the CHANCES consortium. Eur J Epidemiol.

9.Chen GC, Zhang ZL, Wan Z, et al. (2015) Circulating 25-hydroxyvitamin D and risk of lung cancer: a dose-response meta-analysis. Cancer Causes Control. 26: 1719-28.

10.Afzal S, Bojesen SE, Nordestgaard BG. (2013) Low Plasma 25-Hydroxyvitamin D and Risk of Tobacco-Related Cancer. Clin Chem. 59: 771-80.

11.Wong YY, Hyde Z, McCaul KA, et al. (2014) In older men, lower plasma 25-hydroxyvitamin D is associated with reduced incidence of prostate, but not colorectal or lung cancer. PLoS One. 9: e99954.