Department of Surgery, Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America.
Department of Pathology and Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
PLoS One. 2020 Mar 5;15(3):e0229754. doi: 10.1371/journal.pone.0229754. eCollection 2020.
To determine whether SRD5A2 promoter methylation is associated with cancer progression during androgen deprivation therapy (ADT) in CRPC.
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.
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).
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.
在接受雄激素剥夺治疗（ADT）的去势抵抗性前列腺癌（CRPC）中，确定 SRD5A2 启动子甲基化是否与癌症进展相关。
在当地的 CRPC 队列中，从在马萨诸塞州综合医院（MGH）接受经尿道前列腺切除术（TURP）的被诊断为 CRPC 的患者中收集了 42 个前列腺标本。在转移性 CRPC（Met CRPC）队列中，从将接受阿比特龙加 dutasteride 治疗的 CRPC 患者中收集了 12 个转移性活检样本（临床试验 NCT01393730）。作为对照，从因良性前列腺增生（BPH）导致膀胱出口梗阻症状而接受前列腺缩小手术的患者中收集了 36 个良性前列腺标本。测试了 SRD5A2 启动子区域的胞嘧啶-磷酸-鸟嘌呤（CpG）位点的甲基化状态。
与良性前列腺组织相比，CRPC 样本在整个启动子区域显示出更高的 SRD5A2 甲基化（当地 CRPC 队列：P <0.001；Met CRPC 队列：P <0.05）。在当地的 CRPC 队列中，更高的甲基化比率与更好的 OS 相关（R2 = 0.33，P = 0.013）。特定区域（核苷酸-434 至-4 [CpG#-39 至 CpG#-2]）的高甲基化与更好的 OS（11.3±5.8 与 6.4±4.4 年，P = 0.001）和 PFS（8.4±5.4 与 4.5±3.9 年，P = 0.003）相关，截止值为 37.9%。多变量分析表明，SRD5A2 甲基化与 OS 独立相关（整个启动子区域：P = 0.035；特定区域：P = 0.02）。
我们的研究表明，SRD5A2 启动子区域的甲基化，特别是 CpG#-39 至-2 处的甲基化，与接受 ADT 治疗的 CRPC 患者的生存改善显著相关。对 SRD5A2 表观遗传修饰的认识可能会影响管理 CRPC 的现有治疗选择和顺序。
