IJE Advance Access originally published online on November 22, 2005
International Journal of Epidemiology 2006 35(2):222-224; doi:10.1093/ije/dyi231
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Commentary |
Commentary: Vitamin D and colorectal cancer—twenty-five years later
1 Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
2 Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
3 Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA. E-mail: edward.giovannucci{at}channing.harvard.edu
In 1980, Garland and Garland hypothesized that vitamin D status accounted for the inverse association between UV-B radiation exposure and risk of colon cancer.1 The title of their article was posed as a question, ‘do sunlight and vitamin D reduce the likelihood of colon cancer?’ At the time, essentially nothing was known about the biology of vitamin D and colon cancer, and epidemiological data were sparse. Largely stimulated by this article, substantial research in this area has been conducted over the past 25 years. The biological underpinnings of this hypothesis have become quite strong; colorectal cells contain vitamin D receptors, and express 1-alpha-hydroxylase, and are thus able to convert 25(OH) vitamin D into 1,25(OH)2 vitamin D. Activation of these receptors by 1,25(OH)2D induces differentiation and inhibits proliferation, invasiveness, angiogenesis, and metastatic potential. The biological basis of the hypothesis can now be considered strong, if not compelling, and has been reviewed elsewhere.2 This commentary will focus on human studies.
From an epidemiological perspective, the hypothesis that vitamin D lowers cancer risk has been tested in at least six ways. First, given that solar UV-B radiation is the major source of vitamin D for most people, one would predict that greater average UV-B radiation in geographical region of residence would correlate with lower risk of colon cancer. Indeed, it was this approach that Garland and Garland used to formulate the vitamin D–cancer hypothesis. Although such ecological data are informative, one of the potential weaknesses is the inability of adequately controlling for potentially confounding factors. Although a number of studies have been published in the United States, each adding some refinement, the data are essentially generated from the same source and, thus, cannot be considered as entirely independent confirmations of the hypothesis. However, a recent Japanese study calculated Pearson correlation coefficients between averaged annual solar radiation levels from 1961 to 1990 and cancer mortality in the year 2000 in 47 prefectures. After adjustment for regional per capita income and dietary factors, for colon cancer mortality rates, the correlations were –0.53 in men and –0.46 in women, and for rectal cancer, the correlations were –0.53 in men and –0.47 in women.3
A second way that this hypothesis has been examined has been to examine vitamin D intake in relation to risk of colorectal neoplasia. A caveat is that vitamin D intake at typical levels currently does not raise 25(OH)D levels substantially. For example, in a recent analysis in the Nurses' Health Study,4 the difference in plasma 25(OH)D levels between high and low quintiles was 
50 nmol/l, but an increment of 400 IU/day (e.g. four glasses of fortified milk) is expected to increase circulating 25(OH)D by <10 nmol/l. Studies that have examined total vitamin D intake (including supplements that broaden the contrast) have generally found an inverse association with colorectal cancer or adenoma.5,6 Many of these studies controlled for various factors, though uncontrolled confounding could remain.
A third approach has been based on examining pre-diagnostic levels of 25(OH)D in relation to colorectal cancer risk. Garland and colleagues7 were the first to demonstrate an inverse association between blood 25(OH)D level and colorectal cancer risk, albeit in a small study of 34 cases. More recently, this relationship has been confirmed in two larger studies conducted in Finland (n = 146 cases)8 and the United States (n = 193 cases).4 Overall, individuals in the top categories of 25(OH)D had 40–50% lower risk of colorectal cancer. Associations persisted after adjusting for a number of potentially confounding factors. In both studies, the associations were stronger in the distal colorectum.
A fourth approach has been to examine seasonality, as 25(OH)D levels are substantially higher in the summer/fall months in contrast to winter/spring months in the Northern hemisphere, especially at high latitudes. A study based on 115 096 cases and 45 667 deaths from breast, colon, or prostate cancer diagnosed between 1964 and 1992 in Norway found striking 30% reductions in fatality rates for cancers diagnosed in the summer and fall9 compared with the winter. This finding indirectly indicates that a high level of 25(OH)D at the time of diagnosis, and possibly during cancer treatment, may improve the prognosis of colorectal cancer as well as other cancer types. These data are provocative, but alternative explanations to vitamin D are possible. For example, potentially beneficial micronutrients and phytochemicals in fruits and vegetables may be primarily consumed in the summer and autumn months. Nonetheless, the potential importance is great as it suggests that a relatively small time window in which vitamin D status is improved, perhaps at the time of treatment, could have an important effect on survival.
A fifth approach is to examine a composite score based on multiple predictors of 25(OH)D levels in relation to cancer risk. Although region of residence has frequently been used as a surrogate of solar UV-B exposure and, thus, implicitly of vitamin D status, other factors are also important determinants of vitamin D levels. Some important factors include skin pigmentation, dietary and supplemental intakes, body mass index that tends to be correlated inversely with 25(OH)D level, and actual sun exposure.6 Preliminary evidence based on the combined influence of race (a surrogate of skin pigmentation), body mass index, region of residence, vitamin D intake, and physical activity (an indicator of sun exposure) to predict 25(OH)D level in the Health Professionals Follow-Up Study suggests that the men at higher risk of hypovitaminosis D are at increased risk of colorectal cancer.10
A final line of evidence is based on the examination of genetic polymorphisms in the vitamin D pathway in relation to cancer risk. To date, much of the research in this area has been focused on three adjacent restriction fragment length polymorphisms for BMI, ApaI and TaqI at the 3' end of the vitamin D receptor gene.11 These polymorphisms are probably non-functional, but may be in linkage disequilibrium with functional polymorphisms elsewhere in the vitamin D receptor gene. Results to date have been inconclusive. Interestingly, two recent studies based on the Fok1 VDR polymorphism in Asian populations found the F allele associated with a markedly elevated risk compared with the f allele.12,13 The F allele is associated with a VDR protein that is three amino acids shorter than the f allele, supporting functionality of this polymorphism. These Asian populations differ in a number of ways from Western populations. For example, colon cancer rates are lower, populations are leaner, diets differ, and levels and intakes of vitamin D and calcium (a potentially interacting factor) are likely to be lower. In United States populations, the relationship between VDR polymorphisms and colorectal cancer risk may be more complex, and may interact with some of these factors.14,15 The consistent findings in Asian populations further support a role of vitamin D in colorectal cancer in humans, because if vitamin D were not important, VDR polymorphisms should not be directly associated with cancer risk.
A quarter of a century later, can we answer the question ‘do sunlight and vitamin D reduce the likelihood of colon cancer?’ first posed by Garland and Garland?1 The epidemiological findings do not prove that higher levels of vitamin D would lower risk of colorectal cancer, but together with the mechanistic data, they make a fairly compelling case. Each of the six observations summarized above could be potentially explained by confounding, but it is difficult to conceive of a single confounding factor that could explain the findings with regional differences in different countries, vitamin D levels, vitamin D intakes, genetic factors, and seasonal effects. Randomized trials could theoretically provide more definitive answers, but questions of optimal dose and duration of treatment remain. Based on the epidemiological evidence, intakes more than 400 or even 800 IU/day may be required to get clear results, and the required duration is unknown. Moreover, the concern, arguably unjustified,16,17 of vitamin D toxicity tends to make researchers hesitant of administrating substantially higher doses. Confirming that vitamin D indeed accounts for these observations is critical because current health recommendations typically discourage high intakes of vitamin D as well as sun exposure, at least without use of sunscreen, which effectively blocks vitamin D production. However, given our current knowledge, it seems reasonable to recommend 1000 IU/day of vitamin D3, perhaps up to 2000 IU/day, in people getting minimal UV-B exposure.
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1 Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 1980;9:227–31. (Reprinted Int J Epidemiol 2006;35:217–20.)
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4 Feskanich D, Ma J, Fuchs CS et al. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 2004;13:1502–08.
5 Grant WB, Garland CF. A critical review of studies on vitamin D in relation to colorectal cancer. Nutr Cancer 2004;48:115–23.[CrossRef][ISI][Medline]
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7 Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 1989;2:1176–78.[ISI][Medline]
8 Tangrea J, Helzlsouer K, Pietinen P et al. Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men. Cancer Causes Control 1997;8:615–25.[CrossRef][ISI][Medline]
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10 Giovannucci E. The role of vitamin D in cancer incidence and mortality. American Association for Cancer Research Annual Meeting, Anaheim CA, 2005.
11 Uitterlinden AG, Fang Y, van Meurs JB, van Leeuwen H, Pols HA. Vitamin D receptor gene polymorphisms in relation to vitamin D related disease states. J Steroid Biochem Mol Biol 2004;89–90:187–93.
12 Wong HL, Seow A, Arakawa K, Lee HP, Yu MC, Ingles SA. Vitamin D receptor start codon polymorphism and colorectal cancer risk: effect modification by dietary calcium and fat in Singapore Chinese. Carcinogenesis 2003;24:1091–95.
13 Park KS, Woo M, Nam JH et al. Start codon polymorphisms in the vitamin D receptor and colorectal cancer risk. Cancer Lett 2005; (in press).
14 Slattery ML, Murtaugh M, Caan B, Ma KN, Wolff R, Samowitz W. Associations between BMI, energy intake, energy expenditure, VDR genotype and colon and rectal cancers (United States). Cancer Causes Control 2004;15:863–72.[CrossRef][ISI][Medline]
15 Slattery ML, Neuhausen SL, Hoffman M et al. Dietary calcium, vitamin D, VDR genotypes and colorectal cancer. Int J Cancer 2004;111:750–56.[CrossRef][Medline]
16 Vieth R. Why the optimal requirement for Vitamin D3 is probably much higher than what is officially recommended for adults. J Steroid Biochem Mol Biol 2004;89–90:575–79.
17 Vieth R, Kimball S, Hu A et al. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr J 2004;19:8.
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