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9 Molecular Biology of Vitamin D Metabolism and Skin Cancer 203

independent from confounding factors including sex, age, Breslow thickness,
anatomic site, social class, skin awareness, skin self examination and physician
examination [9]
Thus, such epidemiological studies yield interesting results that imply a complex
process in the development of melanoma. Knowing that vitamin D synthesis is
dependant on UV exposure, the effect of sun exposure with increased melanoma
survival raised the possibility of a link between vitamin D and skin cancer.

9.4.2 Polymorphisms of the Vitamin D Receptor

The involvement of 1,25(OH) D in skin cancer is also supported by genetic
2 3
evidence. As the 1,25(OH) D must act via the VDR to elicit the genomic effect and
2 3
a possible VDR to elicit the non-genomic pathway, it is expected that any
mem
changes in the genetic sequence and expression of VDR will have an effect in
1,25(OH) D action, and in turn on skin cancer outcome.
2 3
The most well known polymorphisms in the VDR include the polymorphism
at the 5¢FokI restriction site in exon 2; an alteration in intron 8 to generate the
BsmI and ApaI restriction sites; a synonymous polymorphism in exon 9, generat-
ing a TaqI (t) restriction site and a poly-A microsatellite in the 3¢untranslated
region [8]. The 5¢ FokI restriction site does not seem to show any linkage to the
other polymorphisms, whereas the latter four polymorphisms are in strong link-
age disequilibrium [48]. Thus, in the studies of [76, 97], the analysis of the TaqI
was assumed to represent the 3¢ cluster of polymorphisms. The 5¢FokI polymor-
phism involves a T to C transition at the ATG start site, producing two variants
of the protein, a shorter protein (F) of 424 amino acids (aa) and a longer protein
of 427aa (f) [8]. In one study [76], it was found that a significant reduction in
risk of malignant melanoma (MM) was associated with the FF phenotype. It has
previously been reported that the F allele with the shorter protein of 424 aa had
higher transcriptional activation activity and FokI polymorphism has a func-
tional significance [76]. This was consistent with the finding that the f being a
risk allele [97]. The same study found that the t allele was protective against
melanoma with a tt genotype reducing the risk by 29%. Interestingly, [76] did
not find a significant association with melanoma risk but showed the genotype
combination ttff was significantly associated with tumors of increased Breslow
thickness and which raised the idea that genetic variants of VDR can be a deter-
minant of melanoma outcome. The role of VDR polymorphisms have also been
studied in other cancers such as the breast and colon, however, the results were
not always consistent [77, 79, 153]. These controversies may be due to differ-
ences in vitamin D serum levels and sample variations [97]. It is also thought
that polymorphisms in the 3¢UTR may have cell type specific effect that can play
a role in altered VDR transcription [155]. Furthermore, the possible interactions
of VDR polymorphism haplotypes with other known risk factors can have an
impact on melanoma risk [96].