Circulating 25-hydroxyvitamin D and Survival Outcomes of Colorectal Cancer: Evidence from Population-based Prospective Cohorts and Mendelian Randomisation

Overview

Journal Br J Cancer

Specialty Oncology

Date 2024 Mar 14

PMID 38480934

Authors

Xiaomeng Zhang

Yazhou He

Xue Li

Rasha Shraim

Wei Xu

Lijuan Wang

Susan M Farrington

Harry Campbell

Maria Timofeeva

Lina Zgaga

Peter Vaughan-Shaw

Evropi Theodoratou

Malcolm G Dunlop

Affiliations

Soon will be listed here.

Abstract

Background: To investigate the association between circulating 25-hydroxyvitamin D (25-OHD) and colorectal cancer (CRC) survival outcomes.

Methods: We conducted analyses among the Study of Colorectal Cancer in Scotland (SOCCS) and the UK Biobank (UKBB). Both cancer-specific survival (CSS) and overall survival (OS) outcomes were examined. The 25-OHD levels were categorised into three groups, and multi-variable Cox-proportional hazard models were applied to estimate hazard ratios (HRs). We performed individual-level Mendelian randomisation (MR) through the generated polygenic risk scores (PRS) of 25-OHD and summary-level MR using the inverse-variance weighted (IVW) method.

Results: We observed significantly poorer CSS (HR = 0.65,95%CI = 0.55-0.76,P = 1.03 × 10) and OS (HR = 0.66,95%CI = 0.58-0.75,P = 8.15 × 10) in patients with the lowest compared to those with the highest 25-OHD after adjusting for covariates. These associations remained across patients with varied tumour sites and stages. However, we found no significant association between 25-OHD PRS and either CSS (HR = 0.98,95%CI = 0.80-1.19,P = 0.83) or OS (HR = 1.07,95%CI = 0.91-1.25,P = 0.42). Furthermore, we found no evidence for causal effects by conducting summary-level MR analysis for either CSS (IVW:HR = 1.04,95%CI = 0.85-1.28,P = 0.70) or OS (IVW:HR = 1.10,95%CI = 0.93-1.31,P = 0.25).

Conclusion: This study supports the observed association between lower circulating 25-OHD and poorer survival outcomes for CRC patients. Whilst the genotype-specific association between better outcomes and higher 25-OHD is intriguing, we found no support for causality using MR approaches.

Citing Articles

Pathway Polygenic Risk Scores (pPRS) for the Analysis of Gene-environment Interaction.

Gauderman W, Fu Y, Queme B, Kawaguchi E, Wang Y, Morrison J bioRxiv. 2025; .

PMID: 39763728 PMC: 11702571. DOI: 10.1101/2024.12.16.628610.

References

Zhang X, Gill D, He Y, Yang T, Li X, Monori G . Non-genetic biomarkers and colorectal cancer risk: Umbrella review and evidence triangulation. Cancer Med. 2020; 9(13):4823-4835. PMC: 7333850. DOI: 10.1002/cam4.3051. View

He Y, Timofeeva M, Farrington S, Vaughan-Shaw P, Svinti V, Walker M . Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study. BMC Med. 2018; 16(1):142. PMC: 6090711. DOI: 10.1186/s12916-018-1119-2. View

Maalmi H, Walter V, Jansen L, Boakye D, Schottker B, Hoffmeister M . Association between Blood 25-Hydroxyvitamin D Levels and Survival in Colorectal Cancer Patients: An Updated Systematic Review and Meta-Analysis. Nutrients. 2018; 10(7). PMC: 6073902. DOI: 10.3390/nu10070896. View

Zgaga L, Theodoratou E, Farrington S, Din F, Ooi L, Glodzik D . Plasma vitamin D concentration influences survival outcome after a diagnosis of colorectal cancer. J Clin Oncol. 2014; 32(23):2430-9. DOI: 10.1200/JCO.2013.54.5947. View

Vaughan-Shaw P, Zgaga L, Ooi L, Theodoratou E, Timofeeva M, Svinti V . Low plasma vitamin D is associated with adverse colorectal cancer survival after surgical resection, independent of systemic inflammatory response. Gut. 2019; 69(1):103-111. PMC: 6943245. DOI: 10.1136/gutjnl-2018-317922. View

Maalmi H, Walter V, Jansen L, Chang-Claude J, Owen R, Ulrich A . Relationship of very low serum 25-hydroxyvitamin D levels with long-term survival in a large cohort of colorectal cancer patients from Germany. Eur J Epidemiol. 2017; 32(11):961-971. DOI: 10.1007/s10654-017-0298-z. View

Larsson S, Wolk A . Obesity and colon and rectal cancer risk: a meta-analysis of prospective studies. Am J Clin Nutr. 2007; 86(3):556-65. DOI: 10.1093/ajcn/86.3.556. View

Ng K, Nimeiri H, McCleary N, Abrams T, Yurgelun M, Cleary J . Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial. JAMA. 2019; 321(14):1370-1379. PMC: 6459117. DOI: 10.1001/jama.2019.2402. View

Virtanen J, Nurmi T, Aro A, Bertone-Johnson E, Hypponen E, Kroger H . Vitamin D supplementation and prevention of cardiovascular disease and cancer in the Finnish Vitamin D Trial: a randomized controlled trial. Am J Clin Nutr. 2022; 115(5):1300-1310. PMC: 9071497. DOI: 10.1093/ajcn/nqab419. View

10.

Vaughan-Shaw P, Buijs L, Blackmur J, Theodoratou E, Zgaga L, Din F . The effect of vitamin D supplementation on survival in patients with colorectal cancer: systematic review and meta-analysis of randomised controlled trials. Br J Cancer. 2020; 123(11):1705-1712. PMC: 7686489. DOI: 10.1038/s41416-020-01060-8. View

11.

Xu Y, Qian M, Hong J, Ng D, Yang T, Xu L . The effect of vitamin D on the occurrence and development of colorectal cancer: a systematic review and meta-analysis. Int J Colorectal Dis. 2021; 36(7):1329-1344. DOI: 10.1007/s00384-021-03879-w. View

12.

Kachuri L, Graff R, Smith-Byrne K, Meyers T, Rashkin S, Ziv E . Pan-cancer analysis demonstrates that integrating polygenic risk scores with modifiable risk factors improves risk prediction. Nat Commun. 2020; 11(1):6084. PMC: 7695829. DOI: 10.1038/s41467-020-19600-4. View

13.

Zgaga L, Theodoratou E, Farrington S, Agakov F, Tenesa A, Walker M . Diet, environmental factors, and lifestyle underlie the high prevalence of vitamin D deficiency in healthy adults in Scotland, and supplementation reduces the proportion that are severely deficient. J Nutr. 2011; 141(8):1535-42. PMC: 3361015. DOI: 10.3945/jn.111.140012. View

14.

He Y, Timofeeva M, Zhang X, Xu W, Li X, Din F . Colorectal cancer risk variants rs10161980 and rs7495132 are associated with cancer survival outcome by a recessive mode of inheritance. Int J Cancer. 2021; 148(11):2774-2778. PMC: 8614120. DOI: 10.1002/ijc.33465. View

15.

Revez J, Lin T, Qiao Z, Xue A, Holtz Y, Zhu Z . Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration. Nat Commun. 2020; 11(1):1647. PMC: 7118120. DOI: 10.1038/s41467-020-15421-7. View

16.

Manousaki D, Mitchell R, Dudding T, Haworth S, Harroud A, Forgetta V . Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci. Am J Hum Genet. 2020; 106(3):327-337. PMC: 7058824. DOI: 10.1016/j.ajhg.2020.01.017. View

17.

Cashman K . Vitamin D Deficiency: Defining, Prevalence, Causes, and Strategies of Addressing. Calcif Tissue Int. 2019; 106(1):14-29. DOI: 10.1007/s00223-019-00559-4. View

18.

Burgess S, Thompson S . Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011; 40(3):755-64. DOI: 10.1093/ije/dyr036. View

19.

Brion M, Shakhbazov K, Visscher P . Calculating statistical power in Mendelian randomization studies. Int J Epidemiol. 2013; 42(5):1497-501. PMC: 3807619. DOI: 10.1093/ije/dyt179. View

20.

Burgess S, Scott R, Timpson N, Davey Smith G, Thompson S . Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol. 2015; 30(7):543-52. PMC: 4516908. DOI: 10.1007/s10654-015-0011-z. View