Cancer Causes & Control

, Volume 8, Issue 4, pp 615–625 | Cite as

Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men

  • Joseph Tangrea
  • Kathy Helzlsouer
  • Pirjo Pietinen
  • Philip Taylor
  • Bruce Hollis
  • Jarmo Virtamo
  • Demetrius Albanes


Experimental and human epidemiologic data suggest a protective rolefor vitamin D in large bowel cancer. To investigate this association, weconducted a nested case-control study within a Finnish clinical trial cohort.Cases (n = 146) were participants diagnosed with primary adenocarcinoma ofthe large bowel. Controls were matched (2:1) to cases on age, date ofbaseline blood draw, and study clinic. Prediagnostic serum levels of thevitamin D metabolites, 25-hydroxyvitamin D (25-OH D), and1,25-dihydroxyvitamin D (1,25-DIOHD) were used as primary exposure measures.The baseline geometric-mean serum level of 25-OH D was 11.6 percent lower incases than in controls (12.2 cf 13.8 ug/l, P = 0.01) while serum levels of1,25-DIOH D did not differ by case-control status. No association was seenbetween serum levels of 1,25-DIOH D and large bowel cancer risk. However, theestimated relative risk (RR) of large bowel cancer decreased with increasinglevel of serum 25-OH D and the associa tion was more pronounced for rectalcancer (55 cases; RR by quartile = 1.00, 0.93, 0.77, 0.37; trend P = 0.06).Neither exclusion of early cases nor multivariate adjustment for potentialconfounders materially altered these estimates. There was no evidence ofeffect modification by level of 1,25-dihydroxyvitamin D or with other knownrisk-factors for large bowel cancer.

25-hydroxyvitamin D colorectal cancer Finland men rectal cancer vitamin D 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    American Cancer Society. Cancer Facts and Figures-1994. Atlanta, GA (USA): ACS, 1994.Google Scholar
  2. 2.
    Miller BA, Gloeckler-Ries LA, Hankey BF, et al. SEER Cancer Statistics Review: 1973-1990. Bethesda, MD (USA): National Cancer Institute, 1993.Google Scholar
  3. 3.
    Hakulinen T, Kenward M, Luostarinen T, et al. Cancer in Finland in 1954-2008: incidence, mortality and prevalence by region. Helsinki: Finnish Foundation for Cancer Research, 1989.Google Scholar
  4. 4.
    Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol {dy1980}; 9: 227–31.Google Scholar
  5. 5.
    Gorham ED, Garland CF, Garland FC. Acid haze air pollution and breast and colon cancer mortality in 20 Canadian cities. Can J Public Health {dy1989}; 80: 96–100.Google Scholar
  6. 6.
    Emerson JC, Weiss NS. Colorectal cancer and solar radiation. Cancer Causes Control {dy1992}; 3: 95–9.Google Scholar
  7. 7.
    Garland CF, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Paul O. Dietary vitamin D and calcium and risk of colorectal cancer: a 19 year prospective study in men. Lancet {dy1985}; 1: 307–9.Google Scholar
  8. 8.
    Bostick RM, Potter JD, Sellers TA, McKenzie DR, Kushi LH, Folsom AR. Relation of calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women. Am J Epidemiol {dy1993}; 137: 1302–17.Google Scholar
  9. 9.
    Garland CF, Garland FC, Ko Shaw E, Gorham ED, Comstock GW, Helsing KJ. Serum 25-hydroxyvitamin D and colon cancer: eight year prospective study. Lancet {dy1989}; 2: 1176–8.Google Scholar
  10. 10.
    Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Colon cancer and prediagnostic serum 25-D and 1,25-D levels [Abstract]. In: Norman AW, Bouillon R, Thomasset M, eds. Vitamin D. A Pluripotent Steroid Hormone: Structural Studies, Molecular Endocrinology, and Clinical Applications. Berlin, Germany: de Gruyter, 1994: 494–5.Google Scholar
  11. 11.
    Garland CF, Garland FC, Gorham ED. Can colon cancer incidence and death rates be reduced with calcium and vitamin D? Am J Clin Nutr {dy1991}; 54: 193s–201s.Google Scholar
  12. 12.
    Garland CF, Garland FC, Gorham ED. Colon cancer parallels rickets. In: Lipkin M, Newmark HL, Kelloff G, eds. Calcium, Vitamin D and Prevention of Colon Cancer. Boca Raton, Fl (USA): CRC Press, 1991: 81–108.Google Scholar
  13. 13.
    Ross TK, Darwish HM, DeLuca HF. Molecular biology of vitamin D action. Vitam Horm {dy1994}; 49: 281–326.Google Scholar
  14. 14.
    Haussler MR, McCain TA. Basic and clinical concepts related to vitamin D metabolism and action. NEJM {dy1977}; 297: 974–83.Google Scholar
  15. 15.
    Reichel H, Koeffler HP, Norman AW. The role of the vitamin D endocrine system in health and disease. NEJM {dy1989}; 320: 980–91.Google Scholar
  16. 16.
    DeLuca HF. Vitamin D Metabolism and Function. New York,NY (USA): Springer-Verlag, 1979.Google Scholar
  17. 17.
    Fraser DR. Vitamin D. Lancet {dy1995}; 345: 104–7.Google Scholar
  18. 18.
    Darwish H, DeLuca HF. Vitamin D-regulated gene expression. Crit Rev Eukar Gene Express {dy1993}; 3: 89–116.Google Scholar
  19. 19.
    Abe E, Miyaura H, Sakagami M, et al. Differentiation of mouse myeloid leukemia cells induced by 1, alpha-25-dihydroxyvitamin D3. Proc Natl Acad Sci {dy1981}; 78: 4990–4.Google Scholar
  20. 20.
    Colston KW, Colston MJ, Feldman D. 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology {dy1981}; 108: 1083–6.Google Scholar
  21. 21.
    Frampton RJ, Suva LJ, Eisman JA, et al. Presence of 1,25-dihydroxyvitamin D3 receptors in established human cancer cell lines in culture. Cancer Res {dy1982}; 42: 1116–9.Google Scholar
  22. 22.
    Lointier P, Wargovich MJ, Saez S, Levin B, Wildrick DM, Boman BM. The role of vitamin D3 in the proliferation of a human colon cancer cell line in vitro. Anticancer Res {dy1987}; 7: 817–22.Google Scholar
  23. 23.
    Brehier A, Thomasset M. Human colon cell line HT-29: characterization of the 1,25-dihydroxyvitamin D3 receptor and induction of differentiation by the hormone. J Steroid Biochem {dy1988}; 29: 265–70.Google Scholar
  24. 24.
    Harper KD, Iozzo RV, Haddad JG. Receptors for and bioresponses to 1,25-dihydroxyvitaminDin a human colon carcinoma cell line. Metabolism {dy1989}; 38: 1062–9.Google Scholar
  25. 25.
    Cross HS, Huber C, Peterlik M. Antiproliferative effect of 1,25-dihydroxyvitamin D3 and its analogs on human colon adenocarinoma cells (CACO-2): influence of extracellular calcium. Biochem Biophys Res Commun {dy1991}; 179: 57–62.Google Scholar
  26. 26.
    Thomas MG, Tebbutt S, Williamson RCN. Vitamin D and its metabolites inhibit cell proliferation in human rectal mucosa and a colon cancer cell line. Gut {dy1992}; 33: 1660–3.Google Scholar
  27. 27.
    Shabahang M, Buras RR, Davoodi F, Schumaker LM, Nauta RJ, Evans SR. 1,25-dihydroxyvitamin D3 receptor as a marker of human colon carcinoma cell line differentiation and growth inhibition. Cancer Res {dy1993}; 53: 3712–8.Google Scholar
  28. 28.
    Pence BC, Buddingh F. Inhibition of dietary fat-promoted colon carcinogenesis in rats by supplemental calcium or vitamin D3. Carcinogenesis {dy1988}; 9: 187–90.Google Scholar
  29. 29.
    Sitrin MD, Halline AG, Abrahams C, Brasitus TA. Dietary calcium and vitamin D modulate 1,2-dimethylhydrazineinduced colonic carcinogenesis in the rat [Abstract]. Cancer Res {dy1991}; 51: 5608–13.Google Scholar
  30. 30.
    Beaty MM, Lee EY, Glauert HP. Influence of dietary calcium and vitamin D on colon epithelial cell proliferation and 1,2-dimethylhydrazine-induced colon carcinogenesis in rats fed high fat diets [Abstract]. J Nutr {dy1993}; 123: 144–52.Google Scholar
  31. 31.
    Batchelor AJ, Compston JE. Reduced plasma half-life of radio-labelled 25-hydroxyvitamin D3 in subjects receiving a high-fibre diet. Br J Nutr {dy1983}; 49: 213–6.Google Scholar
  32. 32.
    Punnonen R, Gillespy M, Hahl M, Koskinen T, Notelovitz M. Serum 25-OHD, Vitamin A and vitamin E concentrations in healthy Finnish and Floridian women. Int J Vit Nutr Res {dy1987}; 58: 37–9.Google Scholar
  33. 33.
    Holick MF. Environmental factors that influence the cutaneous production of vitamin D. Am J Clin Nutr {dy1995}; 61(Suppl.): 638s–45s.Google Scholar
  34. 34.
    Lamberg-Allardt C. Vitamin D intake, sunlight exposure and 25-hydroxyvitamin D levels in the elderly during one year. Ann Nutr Metab {dy1984}; 28: 144–50.Google Scholar
  35. 35.
    Beadle PC, Burton JL, Leach JF. Correlation of seasonal variation of 25-hydroxycholecalciferol with UV radiation dose. Br J Dermatol {dy1980}; 103: 289–93.Google Scholar
  36. 36.
    Holmberg I, Larsson A. Seasonal variation of vitamin D3 and 25-hydroxyvitamin D3 in human serum. Clin Chim Acta {dy1980}; 100: 173–4.Google Scholar
  37. 37.
    Sowers JR, Wallace RB, Hollis BW, Lemke JH. Parameters related to 25-OH-D levels in a population-based study of women. Am J Clin Nutr {dy1986}; 43: 621–8.Google Scholar
  38. 38.
    Holick MF. The use and interpretation of assays for vitamin D and its metabolites. J Nutr {dy1990}; 120: 1464–9.Google Scholar
  39. 39.
    The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The alpha-tocopherol, beta carotene lung cancer prevention trial: design, methods, participant characteristics, and compliance. Ann Epidemiol {dy1994}; 4: 1–9.Google Scholar
  40. 40.
    The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. NEJM {dy1994}; 330: 1029–35.Google Scholar
  41. 41.
    World Health Organization. International Classification of Diseases, Ninth Revision. Geneva, Switzerland: WHO, 1997.Google Scholar
  42. 42.
    Kyllonen LEJ, Teppo L, Lehtonen M. Completeness and accuracy of registration of colorectal cancer in Finland. Ann Chir Gynaecol {dy1987}; 76: 185–90.Google Scholar
  43. 43.
    Pearce N. Incidence density matching with a simple SAS computer program. Int J Epidemiol {dy1989}; 18: 981–4.Google Scholar
  44. 44.
    Hollis BW, Kamerud JQ, Selvaag SR, Lorenz JD, Napoli JL. Determination of vitamin D status by radioimmuno assay with an125I-labeled tracer. Clin Chem {dy1993}; 39: 529–33.Google Scholar
  45. 45.
    Hollis BW. Assay of circulating 1,25-dihydroxyvitamin D involving a novel single-cartridge extraction and purification procedure. Clin Chem {dy1986}; 32: 2060–3.Google Scholar
  46. 46.
    Pietinen P, Hartman AM, Haapa E, et al. Reproducibility and validity of dietary assessment instruments: 1. A selfadministered food use questionnaire with a portion size booklet. Am J Epidemiol {dy1988}; 128: 655–66.Google Scholar
  47. 47.
    Devesa SS, Chow WH. Variation in colorectal cancer incidence in the United States by subsite of origin. Cancer {dy1993}; 71: 3819–26.Google Scholar
  48. 48.
    Delattre O, Olschwang S, Law DJ, et al. Multiple genetic alterations in distal and proximal colorectal cancer. Lancet {dy1989}; 2: 353–6.Google Scholar
  49. 49.
    Stewart RJ, Stewart AW, Turnbull PRG, Isbister WH. Sex differences in subsite incidence of large bowel cancer. Dis Colon Rectum {dy1983}; 26: 658–60.Google Scholar
  50. 50.
    Bufill J. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med {dy1990}; 113: 779–88.Google Scholar
  51. 51.
    Offerhaus GJA, Giardiello FM, Tersmette KWF, et al. Ethnic differences in the anatomical location of colorectal adenomatous polyps. Int J Cancer {dy1991}; 49: 641–4.Google Scholar
  52. 52.
    Ponz de Leon M, Sachhetti C, Sassatelli R, Zanghieri G, Roncucci L, Scalmati A. Evidence for the existence of different types of large bowel tumor: suggestions from the clinical data of a population-based registry. J Surg Oncol {dy1990}; 44: 35–43.Google Scholar
  53. 53.
    Faivre J, Bedenne L, Boutron MC, Milan C, Collonges R, Arveux P. Epidemiological evidence for distinguishing subsites of colorectal cancer. J Epidemiol Community Health {dy1989}; 43: 356–61.Google Scholar
  54. 54.
    Launoy G, Pottier D, Gignoux M.Cancer du colon proximal et cancer du colon distal: deux cancers epidemiologiquement differents. Gastroenterol Clin Biol {dy1989}; 13: 255–259.Google Scholar
  55. 55.
    Beart RW, Melton LJ, Maruta M, Dockerty MB, Frydenberg HB, O'Fallon WM. Trends in right and left-sided colon cancer. Dis Colon Rectum {dy1983}; 26: 393–8.Google Scholar
  56. 56.
    West DW, Slattery ML, Robison LM, et al. Dietary intake and colon cancer: sex and anatomic site-specific associations. Am J Epidemiol {dy1989}; 130: 883–94.Google Scholar
  57. 57.
    Pocard M, Salmon RJ, Muleris M, et al. Deux colon-deux cancers? Adenocarcinomes coliques proximal ou distal: arguments en faveur d'une cancerogenese distincte. Bull Cancer {dy1995}; 82: 10–21.Google Scholar
  58. 58.
    SAS Institute, Inc. SAS/STAT Software: the PHREG Procedure, Version 6. Cary, NC (USA): SAS Institute, Inc., 1991; SAS Technical Report P-217.Google Scholar
  59. 59.
    SAS Institute, Inc. SAS/STAT User's Guide, Version 6. 4th Edition. Cary, NC (USA): SAS Institute, Inc., 1989.Google Scholar
  60. 60.
    Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Colon cancer and serum vitamin D metabolite levels 10-17 years prior to diagnosis. Am J Epidemiol {dy1995}; 142: 608–11.Google Scholar
  61. 61.
    Cugini P, Coen G, Scavo D, et al. Circannual versus seasonal variation of longitudinally sampled 25-hydroxycholecalciferol serum levels. Biochem Med {dy1984}; 32: 22–9.Google Scholar
  62. 62.
    Hollis BW. Assessment of vitamin D nutritional and hormonal status: what to measure and how to do it. Calcif Tissue Int {dy1996}; 58: 4–5.Google Scholar
  63. 63.
    Tsang RC, Cruz M, Specker B. Vitamin D in infancy: 25-hydroxyvitamin D, an important bioactive principle in vivo in infancy? In: Norman AW, Bouillon R, Thomasset M, eds. Vitamin D, Gene Regulation, Structure-function Analysis and Clinical Application. Berlin, Germany: de Gruyter, 1991: 739–44.Google Scholar
  64. 64.
    Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ, Shaw S. Evidence for alteration of the vitamin D-endocrine system in obese subjects. J Clin Invest {dy1985}; 76: 370–3.Google Scholar
  65. 65.
    Barger-Lux MJ, Heaney RP, Lanspa SJ, Healy JC, DeLuca HF. An investigation of sources of variation in calcium absorption efficiency. J Clin Endocrinol Metab {dy1995}; 80: 406–11.Google Scholar
  66. 66.
    Bell NH. 25-hydroxyvitamin D3 reverses alteration of the vitamin D-endocrine system in blacks. Am J Med {dy1995}; 99: 597–9.Google Scholar
  67. 67.
    Corder EH, Guess HA, Hulka BS, et al. Vitamin D and prostate cancer: a prediagnostic study with stored sera. Cancer Epidemiol Biomark Prev {dy1993}; 2: 467–72.Google Scholar
  68. 68.
    Corder EH, Friedman GD, Vogelman JH, Orentreich N. Seasonal variation in vitamin D, vitamin D-binding protein and dehydroepiandrosterone: risk of prostate cancer in black and white men. Cancer Epidemiol Biomark Prev {dy1995}; 4: 655–9.Google Scholar
  69. 69.
    Mawer EB, Hayes ME, Heys SE, et al. Constitutive synthesis of 1,25-dihydroxyvitamin D3 by a human small cell lung cancer cell line. J Clin Endocrinol Metab {dy1994}; 79: 554–60.Google Scholar
  70. 70.
    Reitsma PH, Rothberg PG, Astrin SM, et al. Regulation of c-myc gene expression in HL-60 leukemia cells by a vitamin D metabolite. Nature {dy1983}; 306: 492–6.Google Scholar
  71. 71.
    Matsui T, Takahashi R, Mihara K, et al. Cooperative regulation of c-myc expression in differentiation of human promyelocytic leukemia induced by recombinant gamma-interferon and 1,25-dihydroxyvitamin D3. Cancer Res {dy1985}; 45: 4366–71.Google Scholar
  72. 72.
    Manolagas SC, Provedini DM, Murray EJ, Murray SS, Tsonis PA, Spandidos DA. Association between the expression of the c-myc oncogene mRNA and the expression of the receptor protein for 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci {dy1987}; 84: 856–60.Google Scholar
  73. 73.
    Brelvi ZS, Studzinski GP. Inhibition of DNA synthesis by an inducer of differentiation of leukemic cells, 1 alpha, 25-dihydroxyvitamin D3, precedes down regulation of the c-myc gene. J Cell Physiol {dy1986}; 128: 171–9.Google Scholar
  74. 74.
    Eisman JA, Koga M, Sutherland RL, Barkla DH, Tutton PJM. 1,25-dihydroxyvitamin D3 and the regulation of human cancer cell replication. Proc Soc Exp Biol Med {dy1989}; 191: 221–6.Google Scholar
  75. 75.
    Vandewalle B, Wattez N, Lefebvre J. Effects of vitamin D3 derivatives on growth, differentiation and apoptosis in tumoral colonic HT 29 cells: possible implication of intracellular calcium. Cancer Lett {dy1995}; 97: 99–106.Google Scholar
  76. 76.
    Lointier P, Meggouh F, Pezet D, et al. Specific receptors for 1,25-dihydroxyvitamin D3 and human colorectal carcinogenesis. Anticancer Res {dy1989}; 9: 1921–4.Google Scholar
  77. 77.
    Meggouh F, Lointier P, Saez S. Sex steroid and 1,25-dihydroxyvitamin D3 receptors in human colorectal adenocarcinoma and normalmucosa. Cancer Res {dy1991}; 51: 1227–33.Google Scholar
  78. 78.
    Lointier P, Meggouh F, Dechelotte P, et al. 1,25-dihydroxyvitamin D3 receptors and human colon adenocarcinoma. Br J Surg {dy1991}; 78: 435–9.Google Scholar

Copyright information

© Chapman and Hall 1997

Authors and Affiliations

  • Joseph Tangrea
    • 1
  • Kathy Helzlsouer
    • 2
  • Pirjo Pietinen
    • 3
  • Philip Taylor
    • 1
  • Bruce Hollis
    • 4
  • Jarmo Virtamo
    • 1
  • Demetrius Albanes
    • 1
  1. 1.National Cancer Institute, NIHBethesdaUSA
  2. 2.School of Hygiene and Public HealthJohns Hopkins UniversityctyBaltimoreUSA
  3. 3.National Public Health InstituteHelsinkiUSA
  4. 4.Medical University of South CarolinaCharlestonUSA

Personalised recommendations