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Review
. 2017 Apr 11;116(8):1092-1110.
doi: 10.1038/bjc.2017.44. Epub 2017 Mar 16.

The Impact of Vitamin D Pathway Genetic Variation and Circulating 25-hydroxyvitamin D on Cancer Outcome: Systematic Review and Meta-Analysis

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Free PMC article
Review

The Impact of Vitamin D Pathway Genetic Variation and Circulating 25-hydroxyvitamin D on Cancer Outcome: Systematic Review and Meta-Analysis

P G Vaughan-Shaw et al. Br J Cancer. .
Free PMC article

Abstract

Background: Vitamin D has been linked with improved cancer outcome. This systematic review and meta-analysis investigates the relationship between cancer outcomes and both vitamin D-related genetic variation and circulating 25-hydroxyvitamin D (25OHD) concentration.

Methods: A systematic review and meta-analysis of papers until November 2016 on PubMed, EMBASE and Web of Science pertaining to association between circulating vitamin D level, functionally relevant vitamin D receptor genetic variants and variants within vitamin D pathway genes and cancer survival or disease progression was performed.

Results: A total of 44 165 cases from 64 studies were included in meta-analyses. Higher 25OHD was associated with better overall survival (hazard ratio (HR=0.74, 95% CI: 0.66-0.82) and progression-free survival (HR=0.84, 95% CI: 0.77-0.91). The rs1544410 (BsmI) variant was associated with overall survival (HR=1.40, 95% CI: 1.05-1.75) and rs7975232 (ApaI) with progression-free survival (HR=1.29, 95% CI: 1.02-1.56). The rs2228570 (FokI) variant was associated with overall survival in lung cancer patients (HR=1.29, 95% CI: 1.0-1.57), with a suggestive association across all cancers (HR=1.26, 95% CI: 0.96-1.56).

Conclusions: Higher 25OHD concentration is associated with better cancer outcome, and the observed association of functional variants in vitamin D pathway genes with outcome supports a causal link. This analysis provides powerful background rationale to instigate clinical trials to investigate the potential beneficial effect of vitamin D in the context of stratification by genotype.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PRISMA Flowchart of the study selection process.Two studies used the same prostate cancer cohort but one reported on circulating 25OHD and the other on genetic variants, and so both were retained. (Holt et al,2010, 2013) Three publications used the same initial cohort of lung cancer patients but two reported on different subpopulations of patients (according to disease stage) and so were retained, (Zhou et al, 2007; Heist et al, 2008), while a third reported on different exposures to the first two and so was also retained (Zhou et al, 2006). Finally, four studies reported on the same melanoma patient cohort (Newton-Bishop et al, 2009, 2015; Field et al, 2013; Davies et al, 2014) (one paper scored lower in NOS scoring was excluded (Field et al, 2013), while the remaining three, which reported different exposure or outcomes were retained. §Only a single study reported impact of circulating vitamin D-binding protein levels on outcome and so could not be included in the meta-analysis. *Includes only exposures and outcomes included in MA. Articles may report on multiple exposure-outcome pairs hence the sum of the pairs is greater than the number of articles included. For example, several papers studied the effect of more than one SNP for example, Zgaga et al, (Zgaga et al, 2014), while many papers studied the impact on both overall survival or progression-free survival for example, Lohman et al (Lohmann et al, 2015). However, where multiple estimates were extracted, no patient was included more than once for a certain exposure or outcome. † Study authors were contacted to provide HR, RR or OR when not reported; 13 did not respond. ¥ One study (Vrieling et al, 2011) used the same breast cancer cohort as a later, larger study (Vrieling et al, 2014) and as both had the same NOS score, the newer study was included. 25OHD: 25-hydroxyvitamin D; DBP: vitamin D binding protein; HR: hazard ratio; PSA: prostate specific antigen; WOK: Web of Knowledge.
Figure 2
Figure 2
Large variation in definition of vitamin D categories in studies included in systematic review.Where not given in the paper, median 25OHD concentration for categories compared was requested from study authors and if not subsequently available was approximated. Approximation of the median for each category was performed using the cohort and/or category range where available. For categories defined by numerical cutoffs of 25OHD, the median for the lower category was approximated as the lowest reported 25OHD value (or 0 if category range not given) added to the midpoint of the category upper cutoff minus the lowest reported 25OHD value. For example, Bittenbring et al (Bittenbring et al, 2014) reported outcome according to 25OHD <>8 ng ml−1 groups and reported a study cohort range of 4–61.9. The median of the lower category (<8 ng ml−1) was approximated as the lowest value in the range plus the midpoint of the category that is, 4+((8−4)/2)=6. The upper category median was approximated as the category cutoff (that is, the lowest value in that category) added to the midpoint of the lower category. for example, in the Bittenbring et al, paper the median of the upper category was approximated as 8+((8−4)/2)=10. Where the compared categories were tertiles, quartiles or quintiles, the median of the lower category and upper categories was the midpoint of the difference between upper cutoff of the lower category compared and the lower cut-off of the higher category compared divided by the number of groups between two categories compared, either subtracted from the upper cutoff of the lower category or added to the lower cutoff of the higher category, respectively. For example, Bade et al, (Bade et al, 2014) grouped patients by quartile of 25OHD and report a cohort range of 4–59.6 ng ml−1. Q1 is given as 25OHD<9.86 ng ml−1 and Q4 >24.4 ng ml−1. Therefore, the medians of Q1 and Q4 were approximated as follows: Q1(median)=9.86−(((24.4−9.86)/2)/2)=6.225 and Q4(median)=24.4+(((24.4−9.86)/2)/2)=28. Insufficient data were reported in three studies to allow graphical illustration of categories or approximation of median. NA=data not reported; For Tretli et al, study: B=breast; C=colon; L=lung; Ly=lymphoma.
Figure 3
Figure 3
Cancer survival and 25-hydroxyvitamin D concentration: meta-analysis of adjusted hazard ratios.HR are sorted by cancer site and the difference in median between ‘high' and ‘low' vitamin D categories compared. Acute myeloid leukaemia (AML), Chronic Lymphoid Leukaemia (CLL), and subtypes of non- Hodgkin's lymphoma (NHL) (large B-cell lymphoma (DLBCL), T-cell lymphoma (TCL), Follicular Lymphoma (FL) and mantle cell lymphoma (MCL)) Myelodysplastic syndrome (MDS) and primary myelofibrosis (PMF). I2=breast: 0, haematological: 0, colorectal: 0.91, prostate: 0.68, head and neck: 0, pancreatic: 0.66, lung: 0.93, skin: 0, overall cancer: 0.18. Approximated Median in studies using quartiles/tertiles (ng ml−1): Tretli breast (lower: 12.9, upper: 33.9), Tretli Haematological: (lower:14.3, upper: 34.1), Tretli colorectal: (lower:16.4, upper: 38), Tretli lung: (lower:14.3, upper: 34.1), Vrieling: (lower: 10.6, upper: NA), Kelly (NA), Fedirko: (lower:11.8, upper: 33.4), Ng et al (2011): (lower:9.6, upper: 30.7), Zgaga: (lower:4.4, upper: 18.3), Ng et al (2008): (lower:21, upper: 30.6), Liu: (lower:7, upper: 25.4), Zhou: (lower:7.4, upper: 24.5), Heist: (lower:10.4, upper: 23.9), Meyer: (lower:16.2, upper: 34.2), Fang: (NA), Muller: (NA).
Figure 4
Figure 4
Cancer progression and 25-hydroxyvitamin D concentration: meta-analysis of adjusted hazard ratios.HR are sortd by the difference in median between high and low vitamin D levels compared. Acute myeloid leukaemia (AML), Chronic Lymphoid Leukaemia (CLL), and subtypes of non- Hodgkin's lymphoma (NHL) (large B-cell lymphoma (DLBCL), T-cell lymphoma (TCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL)). I2=breast: 0, haematological: 0, colorectal: 0, head and neck: 0, skin: 0 overall cancer: 0. Approximated median in studies using quartiles/tertiles (ng ml−1): Vrieling: (lower: 10.6, upper: NA), Kelly (NA), Meyer: (lower:16.2, upper: 34.2), Ng et al, (2011): (lower:9.6, upper: 30.7).
Figure 5
Figure 5
Cancer survival and vitamin D receptor polymorphisms and other vitamin D-related genetic factors: adjusted meta-analysis.I2 for ApaI: 0.95, BsmI prostate: 0.93, BsmI Lung: 0.93, BsmI colorectal: 0, BsmI All: 0.85, Cdx2 prostate: 0, Cdx2 lung: 0, Cdx2 colorectal: 0, Cdx2 All: 0, FokI Prostate: 0, FokI lung: 0, FokI colorectal: 0, FokI All: 0.83, TaqI breast: 0.88, TaqI skin: 0.46, TaqI all: 0.86, Cyp24a1(1) all: 0.75, Cyp24a1(2) all: 0.67, GC all: 0, Rs2107301 all: 0, Rs4516035: 0, Rs2238135: 0.
Figure 5
Figure 5
Cancer survival and vitamin D receptor polymorphisms and other vitamin D-related genetic factors: adjusted meta-analysis.I2 for ApaI: 0.95, BsmI prostate: 0.93, BsmI Lung: 0.93, BsmI colorectal: 0, BsmI All: 0.85, Cdx2 prostate: 0, Cdx2 lung: 0, Cdx2 colorectal: 0, Cdx2 All: 0, FokI Prostate: 0, FokI lung: 0, FokI colorectal: 0, FokI All: 0.83, TaqI breast: 0.88, TaqI skin: 0.46, TaqI all: 0.86, Cyp24a1(1) all: 0.75, Cyp24a1(2) all: 0.67, GC all: 0, Rs2107301 all: 0, Rs4516035: 0, Rs2238135: 0.
Figure 5
Figure 5
Cancer survival and vitamin D receptor polymorphisms and other vitamin D-related genetic factors: adjusted meta-analysis.I2 for ApaI: 0.95, BsmI prostate: 0.93, BsmI Lung: 0.93, BsmI colorectal: 0, BsmI All: 0.85, Cdx2 prostate: 0, Cdx2 lung: 0, Cdx2 colorectal: 0, Cdx2 All: 0, FokI Prostate: 0, FokI lung: 0, FokI colorectal: 0, FokI All: 0.83, TaqI breast: 0.88, TaqI skin: 0.46, TaqI all: 0.86, Cyp24a1(1) all: 0.75, Cyp24a1(2) all: 0.67, GC all: 0, Rs2107301 all: 0, Rs4516035: 0, Rs2238135: 0.
Figure 6
Figure 6
Cancer progression and vitamin D receptor polymorphisms and other vitamin D-related genetic variants: adjusted meta-analysis.I2 for ApaI: 0, BsmI prostate: 0.52, BsmI breast: 0.1, BsmI All: 0.61, FokI Prostate: 0, FokI All: 0.90, TaqI all: 0, Rs4516035: 0.94, Rs22382679: 0.

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