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

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Presentation on theme: "What are the frequency, distribution and functional effects of vitamin D receptor polymorphisms as related to cancer risk? Prostate cancer Statistics Prof."— Presentation transcript:

1 What are the frequency, distribution and functional effects of vitamin D receptor polymorphisms as related to cancer risk? Prostate cancer Statistics Prof Richard Strange Prof Peter Jones Mr Chris LuscombeProf Maurice Zeegers Dr Tony FryerDr Melisa Blagojevic Dr Paul Hoban Dr Nicholas J Rukin Keele University Medical School Staffordshire, England

2 Proportion tumour free Age at diagnosis (years) Lowest 25% cumulative exposure All other quartiles of exposure UVR and Age at Onset of Prostate Cancer 67.7 years 72.1 years (p=0.006, hazard ratio 1.52) Luscombe et al. Lancet 2001

3 VDR Retinoid X receptor 1,25(OH) 2 D 3 Target cell nucleus Transcription 7 dehydroxycholesterolVitamin D 3 Skin UVR 25(OH)D 3 Liver Kidney Prostate 1,25(OH) 2 D 3 VDRE Other tissues 1α hydroxylase 25(OH)D 3

4 DNA Binding domain Ligand Binding domain 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 Promoter region

5 Single Nucleotide Polymorphism in the VDR gene Human VDR >470 reported SNPs Many have low allele frequency Cdx-2 GATA Fok1 Taq Apa1 Poly A

6 Nejentsev et al Hum Mol Gen 2004 Uitterlinden et al. Gene ’3’ 1f 1e 1a 1d 1b 1c ’UTR C3C2C1B VDR Linkage Disequilibrium Blocks A LD Blocks Cdx-2 GATA Fok1 Taq Apa1 Poly A

7 C/A G/A 64922

8 Functional Effects of VDR Polymorphisms in 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

9 Cdx-2A allele associated with increased binding Cdx-2 protein in vitro Increased transcription activity of VDR Cdx-2 Functional VDR Polymorphism Fok 1 Poly (A) repeats ≥17 A’s scored as ‘long’ (L) ≤15 A’s considered as ‘short’(S) Fok 1427-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) repeatL allele may produce receptor mRNA that is more stable and/or is translated more efficiently into VDR protein than the S allele GATAEMSA demonstrate changes in protein-DNA complex formation & increases VDR promoter activity GATA

10 VDR SNPs and Prostate Cancer Risk Genotype Odds ratio (95% CI) P value 1aGGGCCCReference 1.13 ( ) 0.65 ( ) GATAAAAGGGReference 1.01 ( ) 0.62 ( ) C1-1CCCTTTReference 1.03 ( ) 0.97 ( ) C1-2CCCTTTReference 0.91 ( ) 0.71 ( ) Fok1TTTCCCReference 1.13 ( ) 1.11 ( ) Rukin et al. Cancer Letters 2007; 247: prostate cancer / 320 BPH controls Validated UVR questionnaire DNA samples Data not shown: Intron 3 and Taq P>0.05 1a GATA C1-1 C1-2 Fok1

11 Duration of exposureIntensity of exposure VDR Genetics Low RiskHigh Risk Genetic factors VDR polymorphism Environmental No foreign holidays

12 Prostate Cancer BPHOR (95% CI)P valueOR (95% CI)P valueOR (95% CI)P value 1a GG GC CC 143 (33) 238 (55.4) 50 (11.6) 105 (32.8) 159 (49.7) 56 (17.5) Reference 1.13 ( ) 0.65 ( ) Reference 0.88 ( ) 0.40 ( ) Reference 0.62 ( ) 0.26 ( ) GATA AA AG GG 140 (32.6) 226 (52.6) 64 (14.9) 98 (30.6) 155 (48.4) 67 (20.9) Reference 1.01 ( ) 0.63 ( ) Reference 0.97 ( ) 0.42 ( ) Reference 0.46 ( ) 0.24 ( ) C1-1 CC CT TT 191 (44.5) 192 (44.6) 47 (11.0) 142 (44.4) 36 (11.3) Reference 1.03 ( ) 0.97 ( ) Reference 0.98 ( ) 0.56 ( ) Reference 0.58 ( ) 0.22 ( ) C1-2 CC CT TT 209 (48.6) 181 (42.1) 40 (9.3) 147 (45.9) 136 (42.4) 37 (11.7) Reference 0.91 ( ) 0.71 ( ) Reference 0.74 ( ) 0.32 ( ) Reference 0.58 ( ) 0.18 ( ) Fok1 TT CT TT 166 (38.7) 203 (47.1) 61 (14.2) 135 (42.3) 141 (43.9) 44 (13.8) Reference 1.13 ( ) 1.11 ( ) Reference 1.17 ( ) 1.08 ( ) Reference 0.49 ( ) 0.56 ( ) VDR-Environment Interactions Low SunbathingLow sunbathing No foreign holidays < Median exposure

13 VDR Haplotypes and Outcome Block C Haplotypes Low sunbathing No foreign holidays < Median exposure SNPHaplotypeCopiesOdds ratio (95% CI)P-Value 1-a + GATAC-G Reference 0.44 ( ) 0.19 ( ) C1-1 + C1-2G-G Reference 0.35 ( ) 0.23 ( ) GATA + C1-1G-T Reference 0.37 ( ) 0.20 ( ) Similar effects for other haplotypes, except those with Fok

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

15

16 Vitamin D receptor polymorphism and risk of prostate cancer: A meta-analysis. Ntais et al. Cancer Epidemiol Biomarkers Prev. 2003, 12, 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), ‘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.’ Functional Effects as Related to Cancer?


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