Abstract 1450: Intratumoral CYP27A1 expression in relation to cholesterol synthesis and vitamin D signaling and its association with lethal prostate cancer

Abstract

Abstract Background: Higher intratumoral cholesterol synthesis is associated with a worse prognosis in prostate cancer. A recent study identified the vitamin D-regulated enzyme CYP27A1, which converts cholesterol to 27-hydroxycholesterol, to negatively affect cholesterol synthesis and to be associated with biochemical recurrence. We hypothesized that low CYP27A1 expression occurs in patients with low vitamin D signaling and high intratumoral cholesterol synthesis, and that low CYP27A1 expression is associated with higher risk of lethal prostate cancer. Methods: We studied 404 prostate cancer patients in the prospective Health Professionals Follow-up Study (HPFS) and the Physicians' Health Study (PHS) cohorts. After centralized histopathologic review, we measured tumor expression of CYP27A1, SQLE (as a measure of cholesterol synthesis), and CYP24A1 (as a proxy of vitamin D signaling) using mRNA expression profiling. In subgroups, prediagnostic plasma levels of 25-hydroxyvitamin D (25(OH)D, n = 132) and tumor protein expression of the vitamin D receptor (VDR, n = 300) were also available. Using logistic regression, we estimated odds ratios (ORs) for lethal prostate cancer, defined as prostate cancer mortality or metastases, in contrast to non-lethal disease without metastases after at least eight years of follow up. Results: CYP27A1 expression was weakly positively correlated with expression of the vitamin D target gene CYP24A1 (r = 0.17; p < 0.001) but did not differ by plasma 25(OH)D (p-trend = 0.59) or by VDR expression (p-trend = 0.26). CYP27A1 expression was lower in tumors with higher expression of the second rate-limiting enzyme of cholesterol synthesis, SQLE (r = -0.21; p < 0.001). Tumors with higher Gleason grade had lower CYP27A1 expression (HPFS, p < 0.001; PHS, p = 0.004). Higher CYP27A1 was associated with lower risk of lethal cancer in HPFS (OR for highest vs. lowest quintile of expression, 0.31; 95% CI, 0.13 to 0.73; p-trend = 0.007) and in PHS (OR, 0.10; 95% CI, 0.01 to 0.88; p-trend = 0.043) in univariable models. Combining the cohorts and adjusting for baseline clinical characteristics and SQLE, the OR was 0.30 (95% CI, 0.12 to 0.72; p-trend = 0.009). CYP27A1 was less strongly associated with lethal disease when additionally adjusting for Gleason grade (OR, 0.48; 95% CI, 0.18 to 1.31; p-trend = 0.21). Conclusion: Low CYP27A1 expression is associated with higher cholesterol synthesis and a higher risk of progression to lethal disease among prostate cancer patients, potentially partly due to its association with higher Gleason grade. We found little evidence that intratumoral CYP27A1 expression is associated with circulating 25(OH)D. Our results highlight the importance of the regulation of cholesterol metabolism in prostate cancer progression. Citation Format: Nabeela A. Khan, Konrad H. Stopsack, Emma H. Allott, Travis A. Gerke, Edward L. Giovannucci, Lorelei A. Mucci, Philip W. Kantoff. Intratumoral CYP27A1 expression in relation to cholesterol synthesis and vitamin D signaling and its association with lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1450.