Plasma 25-Hydroxyvitamin D Concentration, VDR polymorphisms and their Interaction are Associated with Survival in Colorectal Cancer PatientsLINA ZGAGA

Associate Professor of Epidemiology

Trinity College Dublin

2Vitamin D and Colorectal Cancer

Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980 Sep;9(3):227-31.

1. Incidence

2. Survival

3The SOCCS study (1999-2006)Study of Colorectal Cancer in Scotland

Case-Control Study

1,598 CRC patients

AJCC stages 1-3

Median Follow-Up:

9 years

diagnosis treatment

recruitment & sampling

DNAVitamin D Receptor Polymorphisms

Circulating 25-HydroxyVitamin D (25-OHD) liquid chromatography-tandem mass spectrometry, LC-MS/MS

DEFICIENT

SUFFICIENT

AT RISK OF DEFICIENCY

HIGH LOW

Deeb, K. K., D. L. Trump and C. S. Johnson (2007). "Vitamin D signalling pathways in cancer: potential for anticancer therapeutics." Nat Rev Cancer 7(9): 684-700.

4Colorectal Cancer-Specific and Overall Survival according to Tertile of Circulating Vitamin D

(A) Colorectal cancer-specific and (B) overall survival (after sampling) according to tertile of post-operative 25-hydroxyvitamin D levels in patients with colorectal cancer: (A) CRC AJCC stage 1, (B) CRC AJCC stage 2, (C) CRC AJCC stage 3, and (D) CRC AJCC stages 1-3.

T1 median: 4.80 ng/mL; T2 median: 10.11 ng/mL; T3 median 18.26 ng/mL

A. B.

P=0.22

P=0.002

P=0.24

P=0.001 P=0.00001

P=0.00001

P=0.16

P=0.072

5Unadjusted and Multivariate Adjusted Hazard Ratios of Death According to May-Adjusted 25-HydroxyVitamin D Tertile.

  Vitamin D tertiles (May-adjusted 25-OHD)

Model 1

tertile 1< 7.25 ng/mL

tertile 27.25-13.25 ng/mL

tertile 3> 13.25ng/mL

P 4HR 95% CI P HR 95% CI P

CRC Mortality                      

Unadjusted ref 0.8 0.63-1.02 0.08 0.66 0.51-0.85 0.001 0.012

Partially adjusted 2 ref 0.83 0.65-1.06 0.14 0.69 0.53-0.89 0.004 0.074

Fully adjusted 3 ref0.81

0.63-1.03 0.09 0.67

0.52-0.87 0.002 0.040

All-Cause Mortality                      

Unadjusted ref 0.78 0.64-0.95 0.01 0.62 0.5-0.77 0.00001 0.00007

Partially adjusted 2 ref 0.78 0.64-0.96 0.02 0.67 0.54-0.83 0.0002 0.0036

Fully adjusted 3 ref  0.77

0.63-0.94 0.01

 0.66

0.53-0.81 0.0001

 0.0015

Footnote:1 Follow-Up from time of sampling until death or censor date. 2 Multivariate model adjusted for age at diagnosis, sex and AJCC stage.3 Multivariate model additionally adjusted for tumor site (colon/rectum), surgery (yes/no), time between definitive treatment

and sampling and season of blood collection.

4 p-value was calculated using May-adjusted 25-OHD as a continuous variable

Abbreviations: N, number of patients; 25-OHD, 25-hydroxyvitamin D; CRC, colorectal cancer; HR, hazard ratio; CI, confidence interval.

6Meta-Analyses

Overall (I-squared = 0.0%, p = 0.544)

Fedirko V (2012)

Study

Tretli S (2012)

Ng K (2008)

ID

Zgaga L (2013)

0.66 (0.55, 0.80)

0.69 (0.50, 0.93)

0.20 (0.04, 1.10)

0.61 (0.31, 1.19)

ES (95% CI)

0.67 (0.52, 0.87)

100.00

37.01

%

1.30

7.88

Weight

53.81

0.66 (0.55, 0.80)

0.69 (0.50, 0.93)

0.20 (0.04, 1.10)

0.61 (0.31, 1.19)

ES (95% CI)

0.67 (0.52, 0.87)

100.00

37.01

%

1.30

7.88

Weight

53.81

11

Overall (I-squared = 19.6%, p = 0.290)

Fedirko V (2012)

Tretli S (2012)

Ng K (2008)

Zgaga L (2013)

ID

Mezawa H (2010)

Study

0.63 (0.54, 0.75)

0.67 (0.50, 0.88)

0.40 (0.10, 1.60)

0.52 (0.29, 0.94)

0.66 (0.53, 0.81)

ES (95% CI)

0.16 (0.04, 0.63)

100.00

32.35

1.34

7.48

57.47

Weight

1.36

%

0.63 (0.54, 0.75)

0.67 (0.50, 0.88)

0.40 (0.10, 1.60)

0.52 (0.29, 0.94)

0.66 (0.53, 0.81)

ES (95% CI)

0.16 (0.04, 0.63)

100.00

32.35

1.34

7.48

57.47

Weight

1.36

%

11

A. Colorectal-Cancer Specific Mortality

A. All-Cause Mortality

Fixed-Effects Meta-Analyses of Adjusted Models.

7Vitamin D Polymorphisms and Colorectal Cancer Mortality

SNP model SNPvit D raw

interaction   SNP

vit D May-

adj

interaction

rs7975232 simple 0.80 0.04 0.81 0.06

with interaction 0.71 0.37 0.79 0.72 0.43 0.78

rs1544410 simple 0.87 0.03 0.86 0.04

with interaction 0.76 0.14 0.63 0.94 0.22 0.83

rs10735810 simple 0.57 0.03 0.55 0.04

with interaction 0.48 0.14 0.64 0.34 0.10 0.46

rs11568820 (AA+AG vs.

GG)simple 0.96 0.04 0.96 0.05

  with interaction 0.05 0.08 0.013   0.06 0.08 0.016

protective alleles

(<=2 vs. 2+)simple 0.45 0.03     0.43 0.04  

  with interaction 0.02 0.004 0.016   0.01 0.001 0.005

Vitamin D

VDR

Cancer Progression

?VDR

Biological Effects

8

Thank you for your attention.

Contact: zgagal@tcd.ie

9Most recent Meta-Analyses(incidence)1. Breast cancer

2. Kidney cancer

3. Non-Hodgkin Lymphoma

4. Non-Hodgkin Lymphoma

5. ovarian cancer

6. Pancreatic cancer

7. colorectal cancer

8. colon

9. rectum

10. sporadic colorectal adenoma

11. sporadic colorectal adenoma

recurrence

12. Prostate cancer

13. aggressive prostate cancer

10UVB Irradiation

UVB

Ozone layer