The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis - PubMed (original) (raw)
Review
. 2017 Apr 11;116(8):1092-1110.
doi: 10.1038/bjc.2017.44. Epub 2017 Mar 16.
Affiliations
- PMID: 28301870
- PMCID: PMC5396104
- DOI: 10.1038/bjc.2017.44
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. 2017.
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
**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
**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
**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). _I_2=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
**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
Cancer survival and vitamin D receptor polymorphisms and other vitamin D-related genetic factors: adjusted meta-analysis._I_2 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
Cancer survival and vitamin D receptor polymorphisms and other vitamin D-related genetic factors: adjusted meta-analysis._I_2 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
Cancer survival and vitamin D receptor polymorphisms and other vitamin D-related genetic factors: adjusted meta-analysis._I_2 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
Cancer progression and vitamin D receptor polymorphisms and other vitamin D-related genetic variants: adjusted meta-analysis._I_2 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.
Comment in
- Reply to 'Comment on 'The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis''.
Zgaga L, Vaughan-Shaw PG, O'Sullivan F, Farrington SM, Theodoratou E, Campbell H, Dunlop MG. Zgaga L, et al. Br J Cancer. 2017 Jul 11;117(2):e4. doi: 10.1038/bjc.2017.185. Epub 2017 Jun 22. Br J Cancer. 2017. PMID: 28641317 Free PMC article. No abstract available. - Comment on 'The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis'.
Braillon A. Braillon A. Br J Cancer. 2017 Jul 11;117(2):e3. doi: 10.1038/bjc.2017.184. Epub 2017 Jun 22. Br J Cancer. 2017. PMID: 28641318 Free PMC article. No abstract available.
Similar articles
- Genetic variations of vitamin D receptor and vitamin D supplementation interaction in relation to serum vitamin D and metabolic traits: a systematic review and meta-analysis.
Ghiasvand R, Rashidian A, Abaj F, Rafiee M. Ghiasvand R, et al. Int J Vitam Nutr Res. 2023 Dec;93(6):535-558. doi: 10.1024/0300-9831/a000762. Epub 2022 Aug 23. Int J Vitam Nutr Res. 2023. PMID: 35997204 Review. - Polymorphisms in VDR, CYP27B1, CYP2R1, GC and CYP24A1 Genes as Biomarkers of Survival in Non-Small Cell Lung Cancer: A Systematic Review.
Pineda-Lancheros LE, Gálvez-Navas JM, Rojo-Tolosa S, Membrive-Jiménez C, Valverde-Merino MI, Martínez-Martínez F, Sánchez-Martín A, Ramírez-Tortosa M, Pérez-Ramírez C, Jiménez-Morales A. Pineda-Lancheros LE, et al. Nutrients. 2023 Mar 21;15(6):1525. doi: 10.3390/nu15061525. Nutrients. 2023. PMID: 36986255 Free PMC article. Review. - Low plasma vitamin D is associated with adverse colorectal cancer survival after surgical resection, independent of systemic inflammatory response.
Vaughan-Shaw PG, Zgaga L, Ooi LY, Theodoratou E, Timofeeva M, Svinti V, Walker M, O'Sullivan F, Ewing A, Johnston S, Din FVN, Campbell H, Farrington SM, Dunlop MG. Vaughan-Shaw PG, et al. Gut. 2020 Jan;69(1):103-111. doi: 10.1136/gutjnl-2018-317922. Epub 2019 Apr 25. Gut. 2020. PMID: 31023832 Free PMC article. - Meta-analyses of vitamin D intake, 25-hydroxyvitamin D status, vitamin D receptor polymorphisms, and colorectal cancer risk.
Touvier M, Chan DS, Lau R, Aune D, Vieira R, Greenwood DC, Kampman E, Riboli E, Hercberg S, Norat T. Touvier M, et al. Cancer Epidemiol Biomarkers Prev. 2011 May;20(5):1003-16. doi: 10.1158/1055-9965.EPI-10-1141. Epub 2011 Mar 4. Cancer Epidemiol Biomarkers Prev. 2011. PMID: 21378269 - Association of polymorphisms in the vitamin D receptor gene and serum 25-hydroxyvitamin D levels in children with autism spectrum disorder.
Coşkun S, Şimşek Ş, Camkurt MA, Çim A, Çelik SB. Coşkun S, et al. Gene. 2016 Aug 22;588(2):109-14. doi: 10.1016/j.gene.2016.05.004. Epub 2016 May 4. Gene. 2016. PMID: 27155524
Cited by
- Serum 25-hydroxyvitamin D concentrations and their impact on all-cause mortality in Parkinson's disease: insights from National Health and Nutrition Examination Survey 1999-2020 data.
Yong Y, Dong H, Zhou Z, Zhu Y, Gu M, Li W. Yong Y, et al. Front Nutr. 2024 Aug 9;11:1423651. doi: 10.3389/fnut.2024.1423651. eCollection 2024. Front Nutr. 2024. PMID: 39183989 Free PMC article. - Vitamin D receptor gene polymorphisms and multiple myeloma: a meta-analysis.
Lyu C, Yin X, Li Z, Wang T, Xu R. Lyu C, et al. Clin Exp Med. 2024 Jun 4;24(1):118. doi: 10.1007/s10238-024-01382-4. Clin Exp Med. 2024. PMID: 38833040 Free PMC article. Review. - Circulating vitamin D level before initiating chemotherapy impacts on the time-to-outcome in metastatic colorectal cancer patients: systematic review and meta-analysis.
Ottaiano A, Iacovino ML, Santorsola M, Facchini S, Iervolino D, Perri F, Nasti G, Quagliariello V, Maurea N, Ronchi A, Facchini BA, Bignucolo A, Berretta M. Ottaiano A, et al. J Transl Med. 2024 Jan 30;22(1):119. doi: 10.1186/s12967-024-04889-2. J Transl Med. 2024. PMID: 38291479 Free PMC article. Review. - Vitamin D and potential effects on cancers: a review.
Sobhi P, Bahrami M, Mahdizadeh F, Fazaeli A, Babaei G, Rezagholizadeh L. Sobhi P, et al. Mol Biol Rep. 2024 Jan 25;51(1):190. doi: 10.1007/s11033-023-09111-y. Mol Biol Rep. 2024. PMID: 38270702 Review. - Vitamin D and Its Receptors in Cervical Cancer.
Dong H, Chen S, Liang X, Cai Q, Zhang X, Xie J, Sun Z. Dong H, et al. J Cancer. 2024 Jan 1;15(4):926-938. doi: 10.7150/jca.87499. eCollection 2024. J Cancer. 2024. PMID: 38230221 Free PMC article. Review.
References
- Ahn HY, Chung YJ, Park KY, Cho BY (2016) Serum 25-hydroxyvitamin D level does not affect the aggressiveness and prognosis of papillary thyroid cancer. Thyroid 26(3): 429–433. - PubMed
- Anderson LN, Cotterchio M, Cole DE, Knight JA (2011) Vitamin D-related genetic variants, interactions with vitamin D exposure, and breast cancer risk among Caucasian women in Ontario. Cancer Epidemiol Biomarkers Prev 20(8): 1708–1717. - PubMed
- Anic GM, Thompson RC, Nabors LB, Olson JJ, Browning JE, Madden MH, Murtagh FR, Forsyth PA, Egan KM (2012) An exploratory analysis of common genetic variants in the vitamin D pathway including genome-wide associated variants in relation to glioma risk and outcome. Cancer Causes Control 23(9): 1443–1449. - PMC - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- 12076/CRUK_/Cancer Research UK/United Kingdom
- 18927/CRUK_/Cancer Research UK/United Kingdom
- MC_PC_U127527198/MRC_/Medical Research Council/United Kingdom
- MC_U127527198/MRC_/Medical Research Council/United Kingdom
- MR/K018647/1/MRC_/Medical Research Council/United Kingdom
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical