In the Physicians’ Health Study, we found an inverse trend of circulating blood 25(OH)D levels with rectal cancer risk, which was in line with the results from some of the previous studies that reported a significant inverse association or trend for rectal cancer (7
). By combining results from the Physicians’ Health Study and the previous seven prospective studies, a meta-analysis of eight prospective studies support a stronger inverse association of circulating blood 25(OH)D levels with rectal cancer risk than with colon cancer risk. Statistically non-significant difference warrants more prospective studies of circulating vitamin D levels and colon and rectal cancers and additionally distal and proximal cancers.
Etiologic differences between colon and rectal cancer, such as differences in the associations with life style modifiers, prevalence of specific gene mutations, and expression levels of specific genes, are commonly described (22
). In a clinical study that examined vitamin D deficiency among 221 colon cancer and 94 rectal cancer patients, severe vitamin D deficiency (defined as 15 ng/mL) was more common among rectal cancer patients than colon cancer patients (25
). Several studies reported difference in associations for vitamin D receptor polymorphisms and calcium or vitamin D by tumor sites. The SS genotype of poly(A) mononucleotide repeat and BB genotype of BsmI were associated with a reduced risk of rectal cancer, not with colon cancer in the presence of low calcium and low energy (26
). There is evidence that the associations for calcium and vitamin D were stronger for more distal and rectal tumors than proximal colon tumors (26
). Also, in a study of molecular marker in rectal tumors, the associations of vitamin D intake and vitamin D receptor polymorphism with TP53 mutation status were present in rectal tumors (28
). These studies further suggest a possible difference in vitamin D-related mechanisms in the pathogenesis of rectal cancer compared with colon cancer.
The lack of a significant inverse association in the Physicians’ Health Study between circulating 25(OH)D levels and colon cancer may be because the association of 25(OH)D is weaker for colon cancer or because most of our blood samples (>70 %) were collected during summer/autumn, which may not fully capture differences in levels throughout the year. One study that examined the associations across seasons found that an inverse association was limited to those whose blood samples were collected during winter (8
). Also, we cannot rule out the possibility of laboratory measurement error or misclassification of one-time baseline measurement of 25(OH)D levels in the Physicians’ Health Study because of the possible changes in vitamin D levels influenced by lifestyle factor modification during the follow-up period or the influence of multivitamin intervention arm from the trial, which started in 1997 and is scheduled to end by 2012.
Only three prospective studies examined the association of circulating 1,25(OH)2D levels with risk of colorectal cancer or colon cancer (7
), and our meta-analysis, including the Physicians’ Health Study, suggests no association. This may be because 1,25(OH)2D is more tightly regulated largely by renal 1-α-hydroxylase activity (29
Vitamin D may reduce the risk of rectal cancer through regulation of progression and differentiation (1
) and inhibition of angiogenesis (3
). In animal studies, vitamin D (the vitamin D3 analogue; EB 1089) improved tumor control by radiation treatment, possibly by promoting apoptosis (4
). However, because vitamin D status is largely dependent on sun exposure, there was limited evidence of inverse associations between total or dietary vitamin D intake and colorectal cancer (30
). In contrast, serum or plasma concentrations of 25(OH)D are regarded as a good biomarker of vitamin D status integrating intake through foods, supplements, and exposure to ultraviolet light.
Each study had only a single measure of plasma vitamin D metabolite levels, which did not allow us to examine changes across time. However, a single measure of vitamin D metabolites has shown to be a useful marker to reflect long-term vitamin D status (31
). We could not investigate the effects of changes in vitamin D, or in other variables during follow-up because only baseline measures were available. However, a significant trend for rectal cancer may suggest that misclassification might not be too serious to exclude the association we observed. Also, we cannot rule out the possible residual confounding because our study did not allow us to adjust for cumulative information on covariates across follow-up time. However, we found no appreciable change in the associations after adjusting for various measured risk factors, suggesting that residual confounding by risk factors may not explain the association observed in the Physicians’ Health Study. Heterogeneity across studies in a meta-analysis may be due to differences in laboratory measurement methods, follow-up periods, seasons of blood draw, exposure to sun light, ethnicity, and prevalence of other interaction factors and unknown/unmeasured confounding factors. Important strengths of our study and meta-analysis include the prospective design in which blood samples were collected before cancer diagnosis.
Taken together, these prospective results support the hypothesis that vitamin D is inversely related to colorectal cancer risk, and that vitamin D is more strongly associated with reduced risk of rectal cancer than colon cancer.