Page 317 - Vitamin D and Cancer

304 M. Fakih et al.

females with subsequent variations in milk intake were excluded (RR = 0.59;
CI: 0.3–1.16) [52]. Several other studies confirmed similar findings of inverse
association between vitamin D intake and colorectal cancer [53–62]. Indeed, in an
analysis of 14 observational studies that investigated oral intake of vitamin D and
subsequent incidence of colorectal cancer, Gorham et al. identified the median
Effective Dose in preventing 50% of the colorectal cancer cases (ED ) to be
50
1,000 IU/day when compared to a reference of 100 IU/day [63].

13.1.2.6 Vitamin D Receptor Polymorphism and Colorectal Cancer

There is ample and well documented evidence suggesting that low serum 25-D
3
level is associated with an increased risk of developing colorectal cancer. The anti
carcinogenesis effects of vitamin D is generally thought to be mediated via
3
1,25-hydroxyvitamin D , the most biologically active form of vitamin D which
3,
3
interacts with VDR to activate key antiproliferative, pro-apoptotic, pro-differentiat-
ing and anti-angiogenesis genes in the colorectal mucosa. Down regulation of VDR
expression and increased cyp24A1 expression in neoplastic colorectal epithelial
cells (when compared to normal colonic epithelial cells) could potentially augment
dysregulation of vitamin D homeostasis at the target tissue and thus perpetuate
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colorectal carcinogenesis.
There are conflicting reports on the association of genetic polymorphisms in
VDR gene and the risk of developing colorectal adenoma and cancers in humans.
Several studies suggest an association between certain VDR polymorphisms and
risk for colorectal adenomas and cancer. A study of 26 patient colorectal cancer
patients and 52 controls found the VDR TtFf or TTFf genotypes to be protective
against colorectal carcinogenesis [64]. Another study of 373 colorectal adenoma
patients and 394 controls demonstrated that VDR Fok1 genotype was associated
with large adenomas in patients on low dietary calcium and vitamin D intake [65].
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However, another study of 239 colorectal adenoma cases and 228 controls reported
that VDR Fok1 polymorphism was not significantly associated with colorectal
adenoma and did not modify the effect of either calcium or vitamin D3 [35]. VDR
Taq1 genotype has similarly not been associated with increased risk of developing
colorectal adenomas [66].
A more recent study of 170 colorectal cancer patients and 122 healthy controls
reported significant down regulation of VDR expression on colonic cancer tissue
compared to normal mucosa. However, this study found no differences in VDR
Bsm1 genotypes in colonic tumor tissues and normal colonic mucosa [67]. Similarly
genotyping studies of VDR Cdx2, Fok1, Bsm1, Apa1 and Taq1 polymorphisms in
546 patients with colorectal adenomas showed that these VDR polymorphisms had
no direct effect on the colorectal adenoma recurrence risk [68]. In summary, current
literature show no clear cut association between VDR polymorphisms and the risk
of developing colorectal adenoma and adenocarcinoma. These reports suggest that
the role of VDR polymorphism on colorectal carcinogenesis may be dependent on
other factors including the dietary vitamin D and calcium intake.
3