A presentation given at the Irish Cancer Society's Survivorship Research Day at the Aviva Stadium, Dublin on Thursday, September 20th, 2013. Plasma 25-Hydroxyvitamin D Concentration, VDR polymorphisms and their Interaction are Associated with Survival in Colorectal Cancer Patients - Lina Zgaga

1. Plasma 25-Hydroxyvitamin D
Concentration, VDR polymorphisms
and their Interaction are Associated
with Survival in Colorectal Cancer
Patients
LINA ZGAGA
Associate Professor of Epidemiology
Trinity College Dublin

2. Vitamin D and Colorectal Cancer 2
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

3. The SOCCS study (1999-2006)
Study of Colorectal Cancer in Scotland
3
Case-Control
Study
1,598
CRC patients
AJCC stages 1-3
Median
Follow-Up:
9 years
diagnosis
treatment
recruitment
& sampling
DNA
Vitamin D Receptor Polymorphisms
Circulating 25-HydroxyVitamin D (25-OHD)
liquid chromatography-tandem mass spectrometry, LC-MS/MS
DEFICIENT SUFFICIENTAT 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.

4. Colorectal 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.
4
P=0.22 P=0.002
P=0.24 P=0.001 P=0.00001
P=0.00001
P=0.16
P=0.072

5. Unadjusted 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 2
7.25-13.25 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
ref 0.81 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.
5

6. Meta-Analyses 6
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.

7. Vitamin D Polymorphisms and
Colorectal Cancer Mortality
SNP model SNP
vit 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
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Vitamin D
VDR
Cancer Progression
?
VDR
Biological Effects

8.  Thank you for your attention.
Contact: zgagal@tcd.ie
8

9. Most 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
1. Prostate cancer
2. aggressive prostate cancer
9

10. UVB Irradiation 10
UVB
Ozone layer