Molecular Characterization of Neuroendocrine-like Bladder Cancer
Molecular Characterization of Neuroendocrine-like Bladder Cancer
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DOI：
10.1158/1078-0432.ccr-18-3558
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发表时间：
2019-07-01
影响因子：
11.5
通讯作者：
Black, Peter C.
中科院分区：
文献类型：
--
作者：
da Costa, Jose Batista;Gibb, Ewan A.;Black, Peter C.
目的：神经内分泌（NE）膀胱癌是一种罕见的侵袭性肿瘤。分子分型研究发现，5%至15%的肌肉浸润性膀胱癌（MIBC）在没有NE组织学的情况下具有与NE相一致的转录组模式。这种ne样亚型的临床意义尚未深入探讨。实验设计：生成从7家机构收集的MIBC的转录组全表达谱，并对“破译膀胱”进行临床应用。使用无监督聚类，我们在前瞻性训练队列（PTC, n = 175）上生成了聚类解决方案，开发了单样本分类器来预测NE肿瘤，并在实验性根治性膀胱切除术（RC）队列（n = 225）上评估了所得模型。随机森林模型最终确定并应用于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。结果：在训练队列（PTC）中，使用84个基因面板的分层聚类显示，在缺乏基础或腔内标记表达的情况下，8名患者（4.6%）具有高度异质性的NE标记表达。在验证队列中，1%至6.6%的病例中发现ne样肿瘤。ne样肿瘤患者的1年无进展生存率明显较差（65% ne样肿瘤vs 82%总体，P = 0.046），在调整临床和病理因素后，全因死亡率风险增加6.4倍（P = 0.001）。免疫组化证实了这些肿瘤的神经元特征。结论：开发了一种单个患者分类器，用于识别具有NE转录组谱的组织学尿路上皮癌患者。这些肿瘤代表了MIBC的高风险亚组，可能需要不同的治疗。
Purpose: 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.Experimental Design: 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; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni- and multivariable survival analyses were used to characterize clinical outcomes.Results: 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; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors.Conclusions: 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.