Department of Pathology
Biochemistry | Cancer Biology | Male Urogenital Diseases | Neoplasms | Pathology | Urology
PURPOSE: To determine whether SRD5A2 promoter methylation is associated with cancer progression during androgen deprivation therapy (ADT) in CRPC.
PATIENTS AND METHODS: In a Local CRPC cohort, 42 prostatic specimens were collected from patients who were diagnosed as CRPC and underwent transurethral resection of the prostate (TURP) at Massachusetts General Hospital (MGH). In a metastatic CRPC (Met CRPC) cohort, 12 metastatic biopsies were collected from CRPC patients who would be treated with abiraterone plus dutasteride (Clinical Trial NCT01393730). As controls, 36 benign prostatic specimens were collected from patients undergoing prostate reduction surgery for symptoms of bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH). The methylation status of cytosine-phosphate-guanine (CpG) site(s) at SRD5A2 promoter regions was tested.
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). In Local CRPC cohort, a higher ratio of methylation was correlated with better OS (R2 = 0.33, P = 0.013). Hypermethylation of specific regions (nucleotides -434 to -4 [CpG# -39 to CpG# -2]) was associated with a better OS (11.3+/-5.8 vs 6.4+/-4.4 years, P = 0.001) and PFS (8.4+/-5.4 vs 4.5+/-3.9 years, P = 0.003) 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).
CONCLUSION: Our study demonstrate that SRD5A2 methylation in promoter regions, specifically at CpG# -39 to -2, is significantly associated with better survival for CRPC patients treated with ADT. Recognition of epigenetic modifications of SRD5A2 may affect the choices and sequence of available therapies for management of CRPC.
DNA methylation, Promoter regions, Treatment guidelines, Prostate cancer, Androgens, Clustering algorithms, Epigenetics, Prostate gland
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Copyright: © 2020 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
Wang Z, Deng T, Long X, Lin X, Wu S, Wang H, Ge R, Zhang Z, Wu CL, Taplin ME, Olumi AF. Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy. PLoS One. 2020 Mar 5;15(3):e0229754. doi: 10.1371/journal.pone.0229754. PMID: 32134978; PMCID: PMC7058338. Link to article on publisher's site
Wang Z, Deng T, Long X, Lin X, Wu S, Wang H, Ge R, Zhang Z, Wu C, Taplin M, Olumi AF. (2020). Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy. Open Access Articles. https://doi.org/10.1371/journal.pone.0229754. Retrieved from https://escholarship.umassmed.edu/oapubs/4197
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