BackgroundRisk 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.MethodsBlood 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).Results629 genes were associated with 25-OHD level (PHIPK2 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]).ConclusionsHigher 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-tumor 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.
