Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States.
Merck & Co., Inc., Kenilworth, NJ, United States.
Carcinogenesis. 2024 Oct 10;45(10):735-744. doi: 10.1093/carcin/bgae055.
High circulating vitamin D levels and supplementation may lower prostate cancer mortality. To probe for direct effects of vitamin D signaling in the primary tumor, we assessed how activation of intratumoral vitamin D signaling in prostate cancer is associated with lethal prostate cancer during long-term follow-up. Among 404 participants with primary prostate cancer in the Health Professionals Follow-up Study and the Physicians' Health Study, we defined a gene score of expected activated intratumoral vitamin D signaling consisting of transcriptionally upregulated (CYP27A1, CYP2R1, RXRA, RXRB, and VDR) and downregulated genes (CYP24A1 and DHCR7). We contrasted vitamin D signaling in tumors that progressed to lethal disease (metastases/prostate cancer-specific death, n = 119) over up to three decades of follow-up with indolent tumors that remained nonmetastatic for >8 years post-diagnosis (n = 285). The gene score was downregulated in tumor tissue compared with tumor-adjacent histologically normal tissue of the same men. Higher vitamin D gene scores were inversely associated with lethal prostate cancer (odds ratio for highest versus lowest quartile: 0.46, 95% confidence interval: 0.21-0.99) in a dose-response fashion and after adjusting for clinical and pathologic factors. This association appeared strongest among men with high predicted plasma 25-hydroxyvitamin D3 and men with body mass index ≥25 kg/m2. Findings were replicated with broader gene sets. These data support the hypothesis that active intratumoral vitamin D signaling is associated with better prostate cancer outcomes and provide further rationale for testing how vitamin D-related interventions after diagnosis could improve prostate cancer survival through effects on the tumor.
高循环维生素 D 水平和补充剂可能降低前列腺癌死亡率。为了探究维生素 D 信号在原发性肿瘤中的直接作用，我们评估了前列腺癌中肿瘤内维生素 D 信号的激活如何与长期随访期间致命性前列腺癌相关。在健康专业人员随访研究和医师健康研究中的 404 名原发性前列腺癌患者中，我们定义了一个预期激活的肿瘤内维生素 D 信号的基因评分，该评分由转录上调（CYP27A1、CYP2R1、RXRA、RXRB 和 VDR）和下调基因（CYP24A1 和 DHCR7）组成。我们比较了在长达 30 多年的随访中进展为致命疾病（转移/前列腺癌特异性死亡，n=119）的肿瘤与在诊断后 8 年以上仍未发生转移的惰性肿瘤（n=285）中的维生素 D 信号。与同一男性的肿瘤相邻组织学正常组织相比，肿瘤组织中的基因评分下调。更高的维生素 D 基因评分与致命性前列腺癌呈负相关（最高与最低四分位数的比值比：0.46，95%置信区间：0.21-0.99），呈剂量反应关系，并在调整临床和病理因素后仍然如此。这种关联在预测血浆 25-羟维生素 D3 水平较高的男性和 BMI≥25 kg/m2 的男性中最强。这些发现与更广泛的基因集相吻合。这些数据支持这样一种假设，即活跃的肿瘤内维生素 D 信号与更好的前列腺癌结局相关，并为进一步测试维生素 D 相关干预措施在诊断后如何通过对肿瘤的影响来改善前列腺癌的生存提供了更多依据。
