Introduction: Black men have a higher risk of prostate cancer (PCa) mortality and also have a higher prevalence of vitamin D deficiency. The VITAL clinical trial showed that patients randomized to 2000 IU of vitamin D3 had a significant reduction in advanced cancers compared to placebo (1.7% vs. 2.1%; HR, 0.83; P = .04). Black men also trended towards lower PCa mortality in that trial. Thus, we sought to investigate prostate cancer responsiveness to vitamin D by evaluating differentially expressed genes (DEG) in Black vs. non-Black men’s prostate tumors in high and low vitamin D states.
Methods: We enrolled 169 men in a cross-sectional study evaluating serum vitamin D status and adverse pathology at radical prostatectomy. We selected 78 men. RNA sequencing was done using punch biopsies of >70% epithelium in the dominant tumor nodule and contralateral benign tissue to assess DEG between Black and non-Black tumors. ChIP-seq for vitamin D receptor (VDR) binding sites was used on RC43T (Black PCa cell line) and LNCaP to identify vitamin D responsive genes. Samples were stratified by vitamin D status (above vs. below race-specific median) and race (Black vs non-Black).
Results: There were 57 Black and 21 non-Black men. There were 39 lower risk tumors (Gleason score = 3+4) and 39 higher risk tumors (GS = 3+4 with tertiary 5). In a high vitamin D state, we found 2,101 DEGs in Black tumors vs normal tissue (Figure 1a) compared to only 15 DEGs in non-Black tumors vs normal tissue (Figure 1b). A direct comparison of Black vs non-Black tumors in a high vitamin D state demonstrated 434 DEGs (Figure 1c). When comparing tumors with above vs below-median vitamin D in all patients, we found 2,992 DEGs. Of these, 1,746 DEGs contained VDR binding sites and were found in RC43T while only 10 DEGs with VDR binding sites were found in LNCaP (Figure 1d).
Conclusions: Vitamin D directly impacts gene expression in prostate cancer. Tumors in Black men express more genes that have VDR binding sites than tumors in non-Black men. Due to this unique relationship, Vitamin D may have a role in chemoprevention for clinically localized prostate cancer in Black men.
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.jpg "Neil A. Mistry, MD, MPH photo")
