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
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