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Original article
Low plasma vitamin D is associated with adverse colorectal cancer survival after surgical resection, independent of systemic inflammatory response
  1. P G Vaughan-Shaw1,
  2. L Zgaga2,
  3. L Y Ooi1,
  4. E Theodoratou3,4,
  5. M Timofeeva1,
  6. V Svinti1,
  7. M Walker1,
  8. F O’Sullivan2,
  9. A Ewing1,
  10. S Johnston5,
  11. F V N Din1,
  12. H Campbell3,
  13. S M Farrington1,
  14. M G Dunlop1
  1. 1 Cancer Research UK Edinburgh Centre and MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  2. 2 Department of Public Health and Primary Care, Trinity College Dublin, Dublin 24, Republic of Ireland
  3. 3 Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
  4. 4 Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  5. 5 Specialist Endocrine Laboratory, NHS Greater Glasgow and Clyde, Glasgow, UK
  1. Correspondence to Professor M G Dunlop; Malcolm.Dunlop{at}igmm.ed.ac.uk

Abstract

Objective We assessed the effect of surgical resection of colorectal cancer (CRC) on perioperative plasma vitamin D (25OHD) and C-reactive protein (CRP) level. We investigated the relationship between circulating vitamin D level and CRC survival.

Design We sequentially sampled 92 patients undergoing CRC resection, and measured plasma 25OHD and CRP. For survival analyses, we assayed 25OHD and CRP in two temporally distinct CRC patient cohorts (n=2006, n=2100) and investigated the association between survival outcome, circulating vitamin D and systemic inflammatory response.

Results Serial sampling revealed a postoperative fall (mean 17.3 nmol/L; p=3.6e-9) in plasma 25OHD (nadir days 1–2). CRP peaked 3–5 days postoperatively (143.1 mg/L; p=1.4e-12), yet the postoperative fall in 25OHD was independent of CRP. In cohort analyses, 25OHD was lower in the 12 months following operation (mean=48.8 nmol/L) than preoperatively (54.8 nmol/L; p=1.2e-5) recovering after 24 months (52.2 nmol/L; p=0.002). Survival analysis in American Joint Committee on Cancer stages I–III demonstrated associations between 25OHD tertile and CRC mortality (HR=0.69; 95% CI 0.46 to 0.91) and all-cause mortality (HR=0.68; 95% CI 0.50 to 0.85), and was independent of CRP. We observed interaction effects between plasma 25OHD and rs11568820 genotype (functional VDR polymorphism) with a strong protective effect of higher 25OHD only in patients with GG genotype (HR=0.51; 95% CI 0.21 to 0.81). We developed an online tool for predicted survival (https://apps.igmm.ed.ac.uk/mortalityCalculator/) that incorporates 25OHD with clinically useful predictive performance (area under the curve 0.77).

Conclusions CRC surgery induces a fall in circulating 25OHD. Plasma 25OHD level is a prognostic biomarker with low 25OHD associated with poorer survival, particularly in those with rs11568820 GG genotype. A randomised trial of vitamin D supplementation after CRC surgery has compelling rationale.

  • colorectal cancer
  • cancer prevention
  • colorectal surgery
  • vitamin D receptor gene

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/gutjnl-2018-317922

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    Footnotes

    • Contributors PGVS, SMF, MD : study design, patient recruitment, data collection, data analysis, manuscript writing. LZ: data collection, data analysis, manuscript writing. LYO, MW: patient recruitment, data collection, data analysis. ET: patient recruitment, data collection, data analysis, manuscript appraisal. MT, AE, SJ, VS, FOS: data analysis, manuscript appraisal. FVND: study design, patient recruitment, data collection, data analysis, manuscript appraisal. HC: manuscript appraisal.

    • Funding This work was supported by CRUK programme grant C348/A18927 (MGD). PGVS was supported by MRC Clinical Research Training Fellowship (MR/M004007/1), a Research Fellowship from the Harold Bridges Bequest and by the Melville Trust for the Care and Cure of Cancer. The work received support from COST Action BM1206. ET is supported by a CRUK Career Development Fellowship (C31250/A22804). FOS was funded by Marie Curie Career Integration Grants (grant number FP7-PEOPLE-2013-CIG SOGVID, project number 631041). This work was also funded by a grant to MGD as project leader with the MRC Human Genetics Unit Centre Grant (U127527202 and U127527198 from 1/4/18). AE is funded by a UKRI Innovation Fellowship. The work was supported by funding for the infrastructure and staffing of the Edinburgh CRUK Cancer Research Centre.

    • Competing interests None declared.

    • Ethics approval The research was approved by the local research ethics committees (13/SS/0248; 11/SS/0109 and 01/0/05) and the National Health Service management (2014/0058; 2013/0014 and 2003/W/GEN/05).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Correction notice This article has been corrected since it published Online First. The first affiliation has been updated.

    • Patient consent for publication Not required.