Methylation of SRD5A2 promoter predicts a better outcome for patients undergoing androgen deprivation therapy in patients with Castration Resistant Prostate Cancer
Zongwei Wang, PhD1, Tuo Deng, MD1, Shulin Wu, MD2, Xueming Lin, MD2, Zhenwei Zhang, PhD3, Chin-Lee Wu, MD2, Mary-Ellen Taplin, MD3, Aria F. Olumi, MD1.
1BIDMC, Boston, MA, 2MGH, Boston, MA, 3Dana Farber Cancer Institute, Boston, MA.
Background: 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, in a well-defined subset of PCa patients, 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 and 36 benign prostatic specimens were studied. The methylation status of CpG site(s) at SRD5A2 promoter regions was tested via Targeted Next-Gen Bisulfite Sequencing (tNGBS). Results: Compared with benign prostatic tissue, CRPC samples demonstrated higher SRD5A2 methylation in the whole promoter region (Local CRPC cohort: P < 0.001; Met CRPC cohort: P <0.05). Hypermethylation of specific regions (nucleotides -434 to -4 [CpG# -39 to CpG# -2]) was associated with a better overall survival (11.3±5.8 vs 6.4±4.4 years, P = 0.001) and progression free survival (8.4±5.4 vs 4.5±3.9 years, P = 0.003) with cutoff value of 37.9%. The protein expression of SRD5A2 was negatively correlated with the ratio of SRD5A2 methylation both in the whole promoter region and in the specific region.Conclusions: Our study demonstrates that SRD5A2 hypermethylation in specific promoter regions of SRD5A2, a condition that favors estrogenic as opposed to an androgenic milieu in the prostate, is significantly associated with better survival in CRPC patients who are treated with ADT. We show that a well-defined subset of prostate cancers with SRD5A2 methylation, specifically at CpG#: -39 to CpG#: -2, predicts better outcomes. 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.
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