# Presentation: 842611

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

- <date/time>

- Sue Ingles, University of Southern California

## Vitamin D receptor gene structure

- <date/time>

**Modified from:**
**d'Alesio, A. et al. Hum. Mol. Genet. 2005 14:3539-3548**

**Vitamin D receptor gene structure**

## Evidence that serum Vitamin D modifies the VDR-prostate cancer relationship

- <date/time>

**Evidence that **_**serum Vitamin D**_** modifies the VDR-prostate cancer relationship**

- Ma 1998 (PHS):  Nested case control study (372 cases)
**BsmI B** _protects_ among those with low 25(OH)D.  **
- Li 2007 (PHS):  Nested case control study (492 cases)
**FokI F** _protects_ 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)

_**Effects of genotype, stratified by serum vitamin D**_

## Evidence that Sunlight modifies the VDR-prostate cancer relationship 

- <date/time>

**Evidence that **_**Sunlight**_** modifies the VDR-prostate cancer relationship **

- Bodiwala 2004 (UK):  368 hospital-based PCa cases vs. BPH controls
**Cdx2 *****A*** & **FokI f** _increase 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 t** _protect_ 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

_**Effects of genotype, stratified by sunlight exposure**_

##  Summary:  evidence for effect modification of VDR-PCa relationship  

- <date/time>

** ****Summary:  evidence for effect modification of VDR-PCa relationship**

|  | Block B
(3’UTR) | Start codon (FokI) | Block C1 (promoter 1C) | Block C2 (promoters 1B, D, A, E) |
| --- | --- | --- | --- | --- |
| PHS | No
(BsmI x 25D disappeared) | Yes
Interaction with low 1,25D? |  | Yes
Cdx2 interacts with 25 & 1,25D? |
| UK | No (TaqI) | Yes
FF protects with high sun | Yes  
C1-2 (-819 bp from FokI) with low sun | Yes 
Cdx2 & GATA with low sun |
| California | Yes
TaqI  t protects with high sun | Yes
F protects with high sun |  | Yes
Cdx2A protects with high sun |

## California Collaborative Study of Advanced Prostate Cancer: A population-based case control study

- <date/time>

**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

## Distribution of cases by stage, grade and ethnicity

- <date/time>

| Stage | NH-White | Hispanic | Af Amer. | Total |
| --- | --- | --- | --- | --- |
| Local | 187 | 132 | 212 | 531 |
| Regional | 607 | 147 | 185 | 939 |
| Distant | 86 | 29 | 52 | 167 |
| Unstaged | 44 | 37 | 48 | 129 |
|  |  |  |  |  |
| Grade |  |  |  |  |
| Low | 552 | 194 | 347 | 1093 |
| High | 349 | 138 | 130 | 617 |
| Unknown | 23 | 13 | 20 | 55 |
| Total | 924 | 345 | 497 | 1766 |

## Sources of vitamin D

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**Sources of vitamin D**

## Data Collection:  Sun exposure index

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**Data Collection:  ****Sun exposure index**

-  100 x [ facultative pigmentation – constitutive pigmentation ] / constitutive pigmentation

## Facultative, but not constitutive, pigmentation is related to PCa risk

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**Facultative, but not constitutive, pigmentation is related to PCa risk**

## PCa risk decreases with increasing sun exposure 

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**PCa risk decreases with increasing sun exposure**** **

## Protective effect of sun is strongest for distant disease

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**Protective effect of sun is strongest for distant disease**

## Sunlight protects against low grade and high grade disease

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**Sunlight protects against low grade and high grade disease**

## Can genetic polymorphisms predict response to sunlight exposure? 

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**Can genetic polymorphisms predict response to sunlight exposure? **

## Protective effect of FokI C (F) is apparent only with higher sunlight exposure

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

- *

- *

## Sunlight is protective only for those carrying a Fok1 C allele

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**Sunlight is protective only for those carrying a Fok1 C allele**

- Fok1 CC/CT
- Trend p<0.01

- Fok1 TT
- Trend p=0.56

- 0.61

- Interaction p=0.04

## Sunlight + “efficient” VDR protects against PCa?

- <date/time>

**Sunlight + “efficient” VDR ****protects against PCa?**

- UV light

**VDR**

**7-dehydrocholesterol**

## Sunlight is protective only among: men with lighter constitutive pigmentation, carrying a protective Fok1 allele 

- <date/time>

**Sunlight is protective only among:**** **men with lighter constitutive pigmentation, carrying a protective Fok1 allele

- Interaction p=0.01

## Summary:  Among white men

- <date/time>

**Summary:  ****Among white men**

- _VDR start codon_ (Fok1) common allele protects against prostate cancer
-  *O**verall* 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)

## Can sunlight protect African American men?

- <date/time>

**Can sunlight protect ****African American men?**

- African
- Americans

- Whites

- African
- Americans

- Whites

## African American men are not protected by sunlight

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**African American men are not protected by sunlight**

## Most African American men carry a protective VDR Fok1 allele 

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**Most African American men carry a protective VDR Fok1 allele **

## LD Block structure in African populations permits fine mapping

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- Nejentsev, et al. Human Molecular Genetics, 2004

## Three VDR loci are independently associated with PCA

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**Three VDR loci are independently associated with PCA**

- Univariate	       Multivariate adjusted

## The protective effect of v25 is stronger with low sun exposure

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**The protective effect of v25 is stronger with low sun exposure**

- Int. P=0.03

## Serum vitamin D levels in healthy men by race

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**Serum vitamin D levels ****in healthy men by race**

**African Americans**

**Whites**

## Conclusions

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**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.

## Acknowledgements

- <date/time>

**Esther John**
**NCCC**

**David Van Den Berg**
**Wei Wang**
**USC**

**Gary Schwartz**
**WFUMC**

**Hui Lee Wong**
**NCI**

**Grant support:  NIH/NCI R01CA84979 (Ingles)**
**California Cancer Research Program:  99-00524V-10258 (Ingles)**
**                                                               ****99-00527V-10182  (John)**

**Acknowledgements**