Rectal Cancer genes down-regulated by Vitamin D (3,200 IU only helped some) ā€“ RCT

Created August 2021

Oral vitamin D supplementation induces transcriptomic changes in rectal mucosa that are linked to anti-tumour effects

BMC Med. 2021 Aug 3;19(1):174. doi: 10.1186/s12916-021-02044-y

P G Vaughan-Shaw 1 2, G Grimes 1 2, J P Blackmur 1 2, M Timofeeva 3 4, M Walker 1 2, L Y Ooi 1 5, Victoria Svinti 1 2, Kevin Donnelly 1 2, F V N Din 1 2, S M Farrington 1 2, M G Dunlop 6 7

Note: 12 weeks is not long enough for everyone to plateau at the new vitamin D level If the study had done one or more of the following, far more people would have benefitted 1. Had the trial last 20 weeks, not just 12 1. Used large daily dosing - say 6,000 IU 1. Started with a loading dose ā€“ say 50,000 IU daily for the first week 1. Added a daily Vitamin D receptor (such as Resveratrol or Questetin) to increase the vitamin D getting to cells 1. Cancer - Colon category starts with the following {include} 1. VitaminDWike pages in BOTH Colon Cancer and Genetics categories {category} 1. VitaminDWike pages in BOTH Colon Cancer and Vitamin D Receptor categories {category}

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Background: The risk for several common cancers is influenced by the transcriptomic landscape of the respective tissue-of-origin. Vitamin D influences in vitro gene expression and cancer cell growth. We sought to determine whether oral vitamin D induces beneficial gene expression effects in human rectal epithelium and identify biomarkers of response.

Methods: Blood and rectal mucosa was sampled from 191 human subjects and mucosa gene expression (HT12) correlated with plasma vitamin D (25-OHD) to identify differentially expressed genes. Fifty subjects were then administered 3200IU/day oral vitamin D3 and matched blood/mucosa resampled after 12 weeks. Transcriptomic changes (HT12/RNAseq) after supplementation were tested against the prioritised genes for gene-set and GO-process enrichment. To identify blood biomarkers of mucosal response, we derived receiver-operator curves and C-statistic (AUC) and tested biomarker reproducibility in an independent Supplementation Trial (BEST-D).

Results: Six hundred twenty-nine genes were associated with 25-OHD level (P < 0.01), highlighting 453 GO-term processes (FDR<0.05). In the whole intervention cohort, vitamin D supplementation enriched the prioritised mucosal gene-set (upregulated gene-set P < 1.0E-07; downregulated gene-set P < 2.6E-05) and corresponding GO terms (P = 2.90E-02), highlighting gene expression patterns consistent with anti-tumour effects.

However, only 9 individual participants (18%) showed a significant response (NM gene-set enrichment P < 0.001) to supplementation. Expression changes in HIPK2 and PPP1CC expression served as blood biomarkers of mucosal transcriptomic response (AUC=0.84 [95%CI 0.66-1.00]) and replicated in BEST-D trial subjects (HIPK2 AUC=0.83 [95%CI 0.77-0.89]; PPP1CC AUC=0.91 [95%CI 0.86-0.95]).

Conclusions: Higher plasma 25-OHD correlates with rectal mucosa gene expression patterns consistent with anti-tumour effects, and this beneficial signature is induced by short-term vitamin D supplementation. Heterogenous gene expression responses to vitamin D may limit the ability of randomised trials to identify beneficial effects of supplementation on CRC risk. However, in the current study blood expression changes in HIPK2 and PPP1CC identify those participants with significant anti-tumour transcriptomic responses to supplementation in the rectum. These data provide compelling rationale for a trial of vitamin D and CRC prevention using easily assayed blood gene expression signatures as intermediate biomarkers of response.

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