Transcriptomic data reveal the prognostic and biological significance of the Vitamin D Receptor (VDR) via pro-immune and anti-proliferative mechanisms in a cohort of 703 primary melanomas


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Sathya Muralidhar1,Julia Newton-Bishop1,Timothy Bishop1,David Adams2,Louise Van Der Weyden2,Jeremie Nsengimana1,Jonathan Laye1,Juliette Randerson-Moor1,Joanna Pozniak1,Joey Mark Diaz1
1University of Leeds,2Wellcome Sanger Institute

Abstract

Background

Increased VDR expression within melanoma primaries has been associated with lower stage disease. However, the genomic basis of this effect remains to be understood. 

 

Method

We used clinical (Melanoma Specific Survival -MSS, AJCC stage, tumour site, etc) and transcriptomic data from 703 treatment-naïve primary melanomas (part of the Leeds Melanoma Cohort- LMC) to assess the prognostic significance of VDR expression. VDR-associated candidate pathways/genes were identified by agnostic bioinformatic analyses, which were validated using tumour infiltrating lymphocytes (TILs) and inferred immune cell scores [1]. Finally, in-vitro and in-vivo experiments were used to establish cause and effect.

Results

VDR expression is protective for MSS independent of stage, site, mitotic rate, and TILs (P=0.008). A genome-wide correlation analysis revealed that VDR expression correlated significantly (FDR<5%) and positively with 2025 genes (enriched for immune signalling pathways) and negatively with 1383 genes (enriched for proliferation pathways). 60% of genes known to have a VDR-binding motif are also correlated with VDR expression in our data set. Concordantly, high-VDR tumours had significantly more TILs (P<0.04) and increased immune cell scores (P<10-16) compared to low-VDR tumours. Interestingly high-VDR expression was not associated with variable median VDR copy number or ‘classic’ VDR polymorphisms. An in-vivo metastatic colonisation assay [2] [3] was used to ascribe causal effect to VDR expression by comparing pulmonary metastases area and CD3+ TILs between stable-transfected B16-BL6:VDR mouse melanoma cells and control  B16-BL6 cells (work in progress).   

Conclusion

We used a large cohort of 703 primary melanomas to demonstrate the prognostic significance of VDR expression. Our study is the first to identify the whole-genome correlates of VDR to be associated with pro-immune and anti-proliferative pathways. Taken together, our study aims to provide causal evidence for the pro-immune and anti-proliferative effects of tumour VDR expression.