Intratumoral vitamin D signaling and lethal prostate cancer.

Autor:	Vaselkiv JB; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States., Shui IM; Merck & Co., Inc., Kenilworth, NJ, United States., Grob ST; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States., Ericsson CI; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States., Giovannucci I; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States., Peng C; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States.; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States., Finn SP; Department of Pathology, Trinity College Dublin, Dublin, Ireland., Mucci LA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States.; Discovery Science, American Cancer Society, Atlanta, GA, United States., Penney KL; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States.; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States., Stopsack KH; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States.; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
Jazyk:	angličtina
Zdroj:	Carcinogenesis [Carcinogenesis] 2024 Oct 10; Vol. 45 (10), pp. 735-744.
DOI:	10.1093/carcin/bgae055
Abstrakt:	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. (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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