What are the frequency, distribution and functional effects of vitamin D receptor polymorphisms as related to cancer risk?

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What are the frequency, distribution and
functional effects of vitamin D receptor
polymorphisms as related to cancer risk?
Dr Nicholas J Rukin Keele University Medical
School Staffordshire, England

• Prostate cancer Statistics
• Prof Richard Strange Prof Peter Jones
• Mr Chris Luscombe Prof Maurice Zeegers
• Dr Tony Fryer Dr Melisa Blagojevic
• Dr Paul Hoban

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UVR and Age at Onset of Prostate Cancer
1.00
All other quartiles of exposure
67.7 years
72.1 years (p0.006, hazard ratio 1.52)
0.50
Proportion tumour free
Lowest 25 cumulative exposure
0.00
50
60
70
80
90
Age at diagnosis (years)
Luscombe et al. Lancet 2001
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UVR
Skin
7 dehydroxycholesterol Vitamin D3
Liver
Kidney
1a hydroxylase
1,25(OH)2D3
25(OH)D3
25(OH)D3
Prostate
Other tissues
Target cell nucleus
Retinoid X receptor
1,25(OH)2D3
VDR
VDRE
Transcription
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Vitamin D Receptor Gene Chr 12q13

• 9 exons, alternatively spliced promoter region
• Binding domains DNA binding domain binds VDRE
• Ligand binding domain 1,25(OH)2 Vit D

DNA Binding domain
Ligand Binding domain
Promoter region
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Single Nucleotide Polymorphism in the VDR gene
Cdx-2 GATA
Fok1
Taq Apa1 Poly A
Human VDR gt470 reported SNPs Many have low allele
frequency
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VDR Linkage Disequilibrium Blocks
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3
1f 1e 1a 1d
1b 1c 2
3 4 5 6 7 8 9
3UTR
C3
C2
C1
B
A
LD Blocks
Cdx-2 GATA
Fok1
Taq Apa1 Poly A
Nejentsev et al Hum Mol Gen 2004 Uitterlinden et
al. Gene 2004
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C/A63935
G/A64922
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Functional Effects of VDR Polymorphismsin the
VDR Null Mice

• Calcium Homeostasis
• Associated with hypocalcaemia,
  hyperparathyroidism, rickets, osteomalacia and
  alopecia
• Carcinogenesis
• DMBA-induced carcinogenesis Increased hormone
  independent tumours, epidermal and lymphoid
  tumour

Zinser et al. J Steroid Biochem Mol Biol. 2005
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Functional VDR Polymorphism
Poly (A) repeats 17 As scored as long (L) 15
As considered as short(S)
GATA
Cdx-2
Fok 1
Cdx-2 A allele associated with increased binding
Cdx-2 protein in vitro Increased transcription
activity of VDR
GATA EMSA demonstrate changes in protein-DNA
complex formation increases VDR promoter
activity
Fok 1 427-residue VDR protein is produced F
allele displays moderately higher transcriptional
activity, as well as greater interaction in
vitro with transcription factor IIB
Poly (A) repeat L allele may produce receptor
mRNA that is more stable and/or is translated
more efficiently into VDR protein than the S
allele
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VDR SNPs and Prostate Cancer Risk

• 430 prostate cancer / 320 BPH controls
• Validated UVR questionnaire
• DNA samples

1a GATA C1-1 C1-2 Fok1
Rukin et al. Cancer Letters 2007 247 328-335
Data not shown Intron 3 and Taq Pgt0.05
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VDR effect is likely to work through a
GENE-ENVIRONMENT interaction
Duration of exposure
Intensity of exposure
VDR Genetics
Genetic factors VDR polymorphism Environmental
No foreign holidays ltmedian exposure Low
sunbathing score Diet
Low Risk
High Risk
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VDR-Environment Interactions
Low Sunbathing
Low sunbathing No foreign holidays lt Median
exposure
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VDR Haplotypes and Outcome

• Block C Haplotypes Low sunbathing
• No foreign holidays
• lt Median exposure

Similar effects for other haplotypes, except
those with Fok
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Conclusion

• VDR structure, SNP choice and haplotypes
• Gene-environmental interaction important
• Replication of results
• Future?

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(No Transcript)
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Vitamin D receptor polymorphism and risk of
prostate cancer A meta-analysis. Ntais et al.
Cancer Epidemiol Biomarkers Prev. 2003, 12,
1395-1402
Functional Effects as Related to Cancer?

• Taq1, Bsm1, poly (A) micro satellite repeats and
  Fok1
• The meta-analysis shows that these four
  polymorphisms are unlikely to be a major
  determinants of susceptibility to prostate cancer
  on a wide population basis.

A systematic review of vitamin D receptor gene
polymorphisms and prostate cancer risk Berndt et
al. J Urol. 2006, 175(5), 1613-23 The
results of this meta-analysis suggest that the
vitamin D receptor TaqI, poly (A), Bsm1,
Apa1 and Fok1 polymorphisms are not related to
prostate cancer risk.