Can diet &/or sunlight modify the relationship between VDR polymorphisms and prostate cancer risk?

1. Can diet &/or sunlight modify the relationship between VDR polymorphisms and prostate cancer risk? Sue Ingles, University of Southern California

2. C3 C2 C1 FokI BsmI TaqI Cdx2 GATA Vitamin D receptor gene structure Modified from: d'Alesio, A. et al. Hum. Mol. Genet. 2005 14:3539-3548

3. Evidence that serum Vitamin D modifies the VDR-prostate cancer relationship Effects of genotype, stratified by serum vitamin D • Ma 1998(PHS):Nested case control study (372 cases) • BsmI Bprotects among those with low 25(OH)D. ** • Li 2007(PHS): Nested case control study (492 cases) • FokI Fprotects among those with low 25(OH)D. ** • Mikhak 2007(PHS): Nested case control study (704 cases) • Cdx2 A plus 25(OH)D deficiency protects (compared to GG, not deficient) ** • Cdx2 A plus 1,25(OH)D deficiency increases risk of aggressive tumors (compared to GG, not deficient) ** • BsmI x 25(OH)D interaction no longer present • FokI x 25(OH)D interaction no longer present • 1,25(OH)2D deficiency increases risk of aggressive disease among those with FokI FF (interaction p=0.06)

4. Evidence that Sunlight modifies the VDR-prostate cancer relationship Effects of genotype, stratified by sunlight exposure • Bodiwala 2004(UK): 368 hospital-based PCa cases vs. BPH controls • Cdx2 A & FokI fincrease risk among those with high sun exposure • TaqI has no effect • John 2005(CA): Pop-based case control study of 450 adv. cases • Cdx2 A (ns), FokI F & TaqI tprotect among those with high exposure • Moon 2006 (UK): 430 hospital-based PCa cases vs. BPH controls • GATA G (in LD with CDX2 A) protects among men with either low or high sun exposure • Rukin 2006(UK): 430 hospital-based PCa cases vs. BPH controls • Block C2 SNPs GATA G and -1521 C protect most strongly among men with low exposure • Block C1 SNP C1-2 related to risk among men with low exposure

5. Summary: evidence for effect modification of VDR-PCa relationship

6. California Collaborative Study of Advanced Prostate Cancer: A population-based case control study Northern California Cancer Center PI: Esther John Cases: SF Bay Area Cancer Registry Controls: Random digit dialing freq. match: age, race/ethnicity University of Southern California PI: Sue Ingles Cases: LA County Cancer Registry Controls: Neighborhood walk freq. match: age, race/ethnicity

7. Distribution of cases by stage, grade and ethnicity

8. Sources of vitamin D

9. Data Collection: Sun exposure index 100 x [ facultative pigmentation – constitutive pigmentation ] / constitutive pigmentation

10. Constitutive Pigmentation (Inner arm) Facultative pigmentation (Forehead) 0.70 Trend p=0.03 Facultative, but not constitutive, pigmentation is related to PCa risk

11. 0.69 Trend p=0.03 PCa risk decreases with increasing sun exposure

12. Regional Trend p=0.15 0.72 0.47 Distant Trend p<0.01 Protective effect of sun is strongest for distant disease

13. Low grade P=0.06 0.66 High grade p=0.03 0.55 Sunlight protects against low grade and high grade disease

14. Fok1 Taq1 Can genetic polymorphisms predict response to sunlight exposure?

15. Protective effect of FokI C (F) is apparent only with higher sunlight exposure * *

16. Sunlight is protective only for those carrying a Fok1 C allele Fok1 TT Trend p=0.56 0.61 Fok1 CC/CT Trend p<0.01 Interaction p=0.04

17. Vitamin D 25(OH)D 1,25(OH)2D Sunlight + “efficient” VDR protects against PCa? VDR UV light 7-dehydrocholesterol

18. Dark skin Trend p=0.87 1.22 Light skin Trend p<0.01 0.27 Sunlight is protective only among:men with lighter constitutive pigmentation, carrying a protective Fok1 allele Interaction p=0.01

19. Summary: Among white men • VDR start codon (Fok1) common allele protects against prostate cancer • Overall approximate 25% reduction in risk • Sun exposure protects against prostate cancer only among: • Men carrying a Fok1 protective allele • 40% reduction in risk (Q5 vs. Q1) • Men with lighter constitutive pigmentation • 70% reduction in risk (Q5 vs. Q1)

20. Can sunlight protect African American men? African Americans African Americans Whites Whites

21. African American men are not protected by sunlight

22. Most African American men carry a protective VDR Fok1 allele

23. LD Block structure in African populations permits fine mapping Nejentsev, et al. Human Molecular Genetics, 2004

24. Three VDR loci are independently associated with PCA Univariate Multivariate adjusted

25. The protective effect of v25 is stronger with low sun exposure Int. P=0.03

26. Serum vitamin D levels in healthy men by race African Americans Whites

27. Conclusions • In whites: • Sunlight can modify the relationship between the VDR Fok1 (start codon) polymorphism and PCa risk. Sunlight decreases risk only for those with F (more active) allele. • In African Americans: • LD block structure allows fine mapping: 3 VDR loci are independently related to PCa risk. • Promoter polymorphism v25 protects against PCa only with low sunlight exposure. • High prevalence of vitamin D insufficiency & deficiency may prevent detection of effect modification by high levels of sunlight exposure. • Dietary supplements may be needed to modify genetic risk in this population.

28. Acknowledgements Esther John NCCC Hui Lee Wong NCI Gary Schwartz WFUMC David Van Den Berg Wei Wang USC Grant support: NIH/NCI R01CA84979 (Ingles) California Cancer Research Program: 99-00524V-10258 (Ingles) 99-00527V-10182 (John)