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Abstract 1449: Intratumoral vitamin D signaling and lethal prostate cancer


 Background: High plasma 25(OH)-vitamin D and vitamin D supplementation may be associated with lower rates of advanced and lethal prostate cancer. We previously found that intratumoral expression of one protein, the vitamin D receptor, was associated with better prognosis among men with prostate cancer. Little data exists about long-term outcomes according to a more comprehensive profile of intratumoral vitamin D signaling.
 Methods: We undertook a comprehensive assessment of intratumoral vitamin D-related gene expression among men diagnosed with prostate cancer in the Health Professionals Follow-up Study (HPFS) and the Physicians’ Health Study (PHS) by creating a score based on gene expression. Of 11 literature-derived candidate genes, 6 genes had sufficient mRNA expression in tumor tissue to include in this study. The equally-weighted vitamin D pathway-related score captured genes that are upregulated (VDR, RXRA, CYP2R1, CYP27A1) and downregulated (DHCR7, CYP24A1) with activation of vitamin D signaling. Higher pathway-related scores reflected expression associated with increased vitamin D signaling. The association between the vitamin D score in prostate tumors and lethal disease (metastases/prostate cancer-specific death) vs. indolent disease (no metastases after >8 years of follow-up) was assessed using logistic regression.
 Results: Among 404 men with prostate cancer, there were 119 lethal events over up to 30 years of follow-up (median: 17 years). Correlations in expression between the six vitamin D-related genes were weak in both tumor tissue (Spearman |r|: 0.03–0.18) and tumor-adjacent histologically normal-appearing tissue (Spearman |r|: 0.00–0.24), consistent with their involvement in multiple signaling pathways. Vitamin D-related genes and the vitamin D pathway score were downregulated in tumor tissue compared to tumor-adjacent histologically normal-appearing tissue (mean difference for the score: -0.35, 95% confidence interval: -0.52 to -0.19). Higher intratumoral vitamin D signaling based on the pathway-related score was inversely associated with lethal prostate cancer even after adjusting for age at diagnosis and Gleason score (odds ratio for the highest vs. lowest quartile: 0.41, 95% CI: 0.19 to 0.86). This inverse association was similar in tumors with and without the TMPRSS2:ERG fusion as well as those with high or low vitamin D receptor protein expression.
 Conclusion: This study of prostate tissue vitamin D-related gene expression provides novel evidence in support of the hypothesis that more active intratumoral vitamin D signaling may lead to better prostate cancer outcomes.
 Citation Format: Jane Bailey Vaselkiv, Sydney T. Grob, Caroline Ericsson, Isabel Giovannucci, Irene Shui, Kathryn L. Penney, Lorelei A. Mucci, Konrad H. Stopsack. Intratumoral vitamin D signaling and lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1449.