Presentation Authors: Tuo Deng, Xueming Lin, Shulin Wu, Zhenwei Zhang, Chin-Lee Wu, Boston, MA, Liying Yan, Hopkinton, MA, Mary-Ellen Taplin, Zongwei Wang, Aria Olumi*, Boston, MA
Introduction: Steroid 5-alpha reductase (SRD5A2) is a critical enzyme for prostatic development and growth. We have found that epigenetic modifications suppress expression of SRD5A2 in one-third of adult prostates, a condition associated with an androgenic to estrogenic switch in adult prostate tissues accounting for changes in hormonal milieu. Our objective is to demonstrate whether the SRD5A2 promoter methylation is associated with cancer progression during androgen deprivation therapy (ADT) in castration-resistant prostate cancer (CRPC).
Methods: 58 CRPC samples were used for testing: 42 CRPC prostate biopsies were collected from Massachusetts General Hospital (MGH), and 16 baseline and progression bone biopsies from patients treated with abiraterone and dutasteride (NCT01393730). As controls, 23 benign prostatic specimens were collected from patients with benign prostatic hyperplasia. The methylation status of CpG site(s) at SRD5A2 promoter regions was tested. Data was retrieved on primary and secondary ADT treatment response. Overall survival (OS) was calculated from time of diagnosis to time of death. The protein expression of SRD5A2 was determined with immunohistochemistry in 42 CRPC samples (MGH), and then correlated to SRD5A2 methylation status.
Results: Compared with benign prostatic tissue, CRPC samples demonstrated higher SRD5A2 methylation in the whole promoter region (MGH samples: P < 0.0001; samples from NCT01393730: P = 0.002). Higher ratio of methylation was correlated with better OS (R2 = 0.11, P = 0.032). Hypermethylation of specific regions (nucleotides -434 to -4 (CpG#: -39 to CpG#: -2)) was associated with a better OS (11.3Â±5.8 vs 6.4Â±4.4 years, P = 0.001) and progression-free survival (PFS, 8.4Â±5.4 vs 4.5Â±3.9 years, P = 0.005) with cutoff value of 37.9%. Multivariate analysis showed that SRD5A2 methylation was associated with OS independently (whole promoter region: P = 0.035; specific region: P = 0.02). The protein expression of SRD5A2 was negatively correlated with its methylation ratio both in the whole promoter region (R2 = 0.235, P = 0.0011) and specific region (CpG#: -39 to CpG#: -2) (R2 = 0.287, P = 0.0003).
Conclusions: Our study show that SRD5A2 hypermethylation in promoter regions, specifically at CpG#: -39 to CpG#: -2, a condition that favors estrogenic as opposed to an androgenic milieu in the prostate, is significantly associated with better survival in CRPC patients treated with ADT. Recognition of epigenetic modifications of SRD5A2, which affects the prostatic hormonal environment, may affect the choices and sequence of available therapies for management of CRPC.
Source of Funding: NIH/R01 DK091353