Department of Urology, CHA Bundang Medical Center, CHA University College of Medicine, Seongnam, South Korea.
Department of Urology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.
J Cancer Res Clin Oncol. 2018 Sep;144(9):1665-1683. doi: 10.1007/s00432-018-2685-6. Epub 2018 Jun 12.
To evaluate associations between pathologic factors and erythroblast transformation-specific (ETS)-related gene (ERG) expression in prostate cancer patients. Using next-generation sequencing, we identified target genes and regulatory networks.
ERG expression in 60 radical prostatectomies was compared with pathological findings by association rule mining with the Apriori algorithm. Whole-exome and RNA sequencing were performed on three formalin-fixed, paraffin-embedded ERG-positive and negative prostate cancer samples. A network diagram identifying dominant altered genes was constructed using Cytoscape open-source bioinformatics platform and GeneMania plugin.
Pathologic conditions positive for perineural invasion, apical margins, and Gleason score 3 + 4 = 7 were significantly more likely to be ERG-positive than other pathologic conditions (p = 0.0008), suggesting an association between ERG positivity, perineural invasion, apical margins, and Gleason score 3 + 4 = 7 (Firth's logistic regression: OR 42.565, 95% CI 1.670-1084.847, p = 0.0232). Results of whole-exome and RNA sequencing identified 97 somatic mutations containing common mutated genes. Regulatory network analysis identified NOTCH1, MEF2C, STAT3, LCK, CACNA2D3, PCSK7, MEF2A, PDZD2, TAB1, and ASGR1 as pivotal genes. NOTCH1 appears to function as a hub, because it had the highest node degree and betweenness. NOTCH1 staining was found 8 of 60 specimens (13%), with a significant association between ERG and NOTCH1 positivity (p = 0.001).
Evaluating the association between ERG expression and pathologic factors, and identifying the regulatory network and pivotal hub may help to understand the clinical significance of ERG-positive prostate cancer.
评估前列腺癌患者中病理因素与红细胞生成素转化特异性（ETS）相关基因（ERG）表达之间的关联。使用下一代测序，我们确定了靶基因和调控网络。
通过 Apriori 算法的关联规则挖掘，比较 60 例根治性前列腺切除术患者 ERG 的表达与病理发现。对 3 例福尔马林固定、石蜡包埋的 ERG 阳性和阴性前列腺癌样本进行全外显子组和 RNA 测序。使用 Cytoscape 开源生物信息学平台和 GeneMania 插件构建识别优势改变基因的网络图。
神经周围侵犯、顶端边缘和 Gleason 评分 3+4=7 的病理情况比其他病理情况更有可能为 ERG 阳性（p=0.0008），提示 ERG 阳性与神经周围侵犯、顶端边缘和 Gleason 评分 3+4=7 之间存在关联（Firth 逻辑回归：OR 42.565，95%CI 1.670-1084.847，p=0.0232）。全外显子组和 RNA 测序的结果确定了 97 个包含常见突变基因的体细胞突变。调控网络分析确定了 NOTCH1、MEF2C、STAT3、LCK、CACNA2D3、PCSK7、MEF2A、PDZD2、TAB1 和 ASGR1 作为关键基因。NOTCH1 似乎作为一个枢纽发挥作用，因为它具有最高的节点度和中间性。在 60 个标本中的 8 个（13%）中发现了 NOTCH1 染色，ERG 与 NOTCH1 阳性之间存在显著相关性（p=0.001）。
评估 ERG 表达与病理因素之间的关联，以及确定调控网络和关键枢纽，可能有助于理解 ERG 阳性前列腺癌的临床意义。
