Page 23 - Vitamin D and Cancer

10 H.S. Cross

treatment with 1,25-(OH) D only [87]. In colon tumors, a CYP24A1 splice variant
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at 754 bp was much more prominent in differentiated (G1) tumors than in undif-
ferentiated ones [25]. In colon cells derived from a G2 tumor, the normal CYP24A1
band as well as the variant were present with similar intensity, but the variant was
not found in differentiated Caco-2 cells. This particular splice variant also disap-
peared after treatment with 1,25-(OH) D [45].
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Studies of genetic polymorphisms with respect to vitamin D hydroxylases are
rare. In colon cancer patients, genetic variants of several markers, among them
the VDR, were investigated to explore associations with microsatellite instability
(MSI) or the CpG Island methylator phenotype (CIMP). Fok1 VDR polymor-
phism was associated with CIMP-positive tumors [88]. When investigating pros-
tate tumors in a group of Caucasian and African American patients, several
non-coding SNPs were identified in the CYP27B1 gene. However, these SNPs
probably do not enhance susceptibility to tumors since they were found also in an
unaffected control group [89]. Novel SNPs were detected in the human CYP24A1
promoter that did result in reduced expression of CYP24A1. This variant was
found primarily in the African American population [90]. Since this population
group is recognized to suffer from vitamin D insufficiency and to present with
prostate tumors more frequently than Caucasian Americans, a relevance of this
variant for protection against tumor incidence by the vitamin D system appears
questionable.

1.2.5 Epigenetic Regulation of CYP27B1 and of CYP24A1
Expression

DNA methylation of cytosine residues of CpG islands in the promoter region of
genes is associated with transcriptional silencing of gene expression in mammalian
cells, while decreased methylation of CpG islands enhances gene activity. The CpG
island methylator phenotype (CIMP) is a distinct phenotype in sporadic colorectal
cancer. For instance, a CIMP-high status is significantly associated with tumors of
the proximal colon. Also relative survival can be associated with methylation status
[91]. While these studies certainly are not definitive yet, it seems unlikely that
methylation/demethylation processes in general can be associated with colon tumor
incidence; though CIMP status coupled with other information such as microsatel-
lite instability could be used as a prognostic factor. However, methylation/demethy-
lation processes concerning promoters of certain genes may predispose to, or
protect against, sporadic malignancies.
In the normal colon, methylation is age- and also apparently site-related. When
evaluating the promoter region of the estrogen receptor (ESR1), it was found to be
more highly methylated (inactivated) in the human distal than in the proximal colon
[72]. Since estrogen apparently enhances 1,25-(OH) D synthesis in mucosal cells,
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this suggests that in women the distal colon is less protected by vitamin D against
tumor incidence (see Sect. 1.2.3.).