Batista da Costa José, Gibb Ewan A, Bivalacqua Trinity J, Liu Yang, Oo Htoo Zarni, Miyamoto David T, Alshalalfa Mohammed, Davicioni Elai, Wright Jonathan, Dall'Era Marc A, Douglas James, Boormans Joost L, Van der Heijden Michiel S, Wu Chin-Lee, van Rhijn Bas W G, Gupta Shilpa, Grivas Petros, Mouw Kent W, Murugan Paari, Fazli Ladan, Ra Seong, Konety Badrinath R, Seiler Roland, Daneshmand Siamak, Mian Omar Y, Efstathiou Jason A, Lotan Yair, Black Peter C
Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
GenomeDx Inc., Vancouver, British Columbia, Canada.
Clin Cancer Res. 2019 Jul 1;25(13):3908-3920. doi: 10.1158/1078-0432.CCR-18-3558. Epub 2019 Apr 5.
Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth.
Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort ( = 225). A random forest model was finalized and applied to 5 validation cohorts ( = 1302). Uni- and multivariable survival analyses were used to characterize clinical outcomes.
In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65% NE-like vs. 82% overall; = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality ( = 0.001). IHC confirmed the neuronal character of these tumors.
A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.
神经内分泌（NE）膀胱癌是一种罕见且侵袭性强的变异类型。分子亚型研究发现，5%至15%的肌层浸润性膀胱癌（MIBC）在无NE组织学特征的情况下具有与NE膀胱癌一致的转录组模式。这种NE样亚型的临床意义尚未得到深入探讨。
对从7家机构收集的MIBC以及Decipher Bladder的临床应用进行全转录组表达谱分析。使用无监督聚类，我们在前瞻性训练队列（PTC；n = 175）上生成了一个聚类解决方案，开发了单样本分类器以预测NE肿瘤，并在测试根治性膀胱切除术（RC）队列（n = 225）上评估所得模型。最终确定了一个随机森林模型并应用于5个验证队列（n = 1302）。采用单变量和多变量生存分析来描述临床结果。
在训练队列（PTC）中，使用84个基因的面板进行层次聚类显示，有一组8例患者（4.6%）在无基底或腔面标志物表达的情况下，NE标志物表达高度异质性。在验证队列中，1%至6.6%的病例被鉴定为NE样肿瘤。NE样肿瘤患者的1年无进展生存率显著更差（NE样为65%，总体为82%；P = 0.046），并且在调整临床和病理因素后，全因死亡风险增加了6.4倍（P = 0.001）。免疫组化证实了这些肿瘤的神经特征。
开发了一种单患者分类器，可识别具有NE转录组特征的组织学尿路上皮癌患者。这些肿瘤代表了MIBC的一个高危亚组，可能需要不同的治疗方法。
