Li Yinan, Zhang Qingfu, Lovnicki Jessica, Chen Ruiqi, Fazli Ladan, Wang Yuzhuo, Gleave Martin, Huang Jiaoti, Dong Xuesen
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Department of Pathology, Duke University School of Medicine, Durham, North Carolina.
Prostate. 2019 Jan;79(1):96-104. doi: 10.1002/pros.23715. Epub 2018 Aug 28.
Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of castrate-resistant prostate cancer characterized by poor patient outcome. Whole transcriptome sequencing analyses identified a NEPC-specific RNA splicing program that is predominantly controlled by the SRRM4 gene, suggesting that SRRM4 drives NEPC development. However, whether SRRM4 expression in patients may aid pathologists in diagnosing NEPC and predicting patient survival remains to be determined. In this study, we have applied RNA in situ hybridization and immunohistochemistry assays to measure the expressions of SRRM4, NEPC markers (SYP, CD56, and CHGA), and adenocarcinoma (AdPC) markers (AR, PSA) in a series of tissue microarrays constructed from castrate-resistant prostate tumors, treatment-naïve tumors collected from radical prostatectomy, and tumors treated with neoadjuvant hormonal therapy (NHT) for 0-12 months. Three pathologists also independently evaluated tumor histology and NEPC marker status. Here, we report that SRRM4 in castrate-resistant tumors is highly expressed in NEPC, strongly correlated with SYP, CD56, and CHGA expressions (Pearson correlation r = 0.883, 0.675, and 0.881; P < 0.0001) and negatively correlated with AR and PSA expressions (Pearson correlation r = -0.544 and -0.310; P < 0.05). Overall survival is 12.3 months for patients with SRRM4 positive tumors, comparing to 23 months for patients with SRRM4 negative tumors. In treatment-naïve AdPC, low SRRM4 expression is detected in ∼16% tumor cores. It correlates with SYP and CHGA expressions, but not Gleason scores. AdPC treated with >7 month NHT has significantly higher SRRM4 expression. Based on these findings, we conclude that SRRM4 expression in castrate-resistant tumors is highly correlated with NEPC and poor patient survival. It may serve as a diagnosis and prognosis biomarker of NEPC.
神经内分泌前列腺癌（NEPC）是去势抵抗性前列腺癌的一种侵袭性亚型，其特征是患者预后较差。全转录组测序分析确定了一种主要由SRRM4基因控制的NEPC特异性RNA剪接程序，这表明SRRM4驱动NEPC的发展。然而，患者中SRRM4的表达是否有助于病理学家诊断NEPC并预测患者生存仍有待确定。在本研究中，我们应用RNA原位杂交和免疫组织化学分析，在一系列组织微阵列中检测SRRM4、NEPC标志物（SYP、CD56和CHGA）以及腺癌（AdPC）标志物（AR、PSA）的表达，这些组织微阵列由去势抵抗性前列腺肿瘤、根治性前列腺切除术中收集的未经治疗的肿瘤以及接受新辅助激素治疗（NHT）0至12个月的肿瘤构建而成。三名病理学家还独立评估了肿瘤组织学和NEPC标志物状态。在此，我们报告，在去势抵抗性肿瘤中，SRRM4在NEPC中高表达，与SYP、CD56和CHGA的表达强烈相关（Pearson相关系数r分别为0.883、0.675和0.881；P<0.0001），与AR和PSA的表达呈负相关（Pearson相关系数r分别为-0.544和-0.310；P<0.05）。SRRM4阳性肿瘤患者的总生存期为12.3个月，而SRRM4阴性肿瘤患者为23个月。在未经治疗的AdPC中，约16%的肿瘤核心检测到低SRRM4表达。它与SYP和CHGA的表达相关，但与Gleason评分无关。接受>7个月NHT治疗的AdPC中SRRM4表达显著更高。基于这些发现，我们得出结论，去势抵抗性肿瘤中SRRM4的表达与NEPC以及患者不良生存高度相关。它可能作为NEPC的诊断和预后生物标志物。
