Institute of Pathology, University of Bern, Switzerland.
Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland.
Urol Oncol. 2019 Sep;37(9):573.e19-573.e29. doi: 10.1016/j.urolonc.2019.06.021. Epub 2019 Jul 26.
The sarcomatoid morphology of muscle-invasive bladder cancer (MIBC) is associated with unfavorable prognosis. However, the genomic, transcriptomic, and proteomic relationship between conventional urothelial and synchronous sarcomatoid morphology is poorly defined.
We compiled a cohort of 21 MIBC patients with components of conventional urothelial and adjacent sarcomatoid morphology within the same tumor focus. We performed comprehensive pathologic and immunohistochemical characterization and in 4 selected cases, subjected both morphologic components to targeted DNA sequencing and whole transcriptome analysis.
Synchronous sarcomatoid and urothelial morphology from the same MIBC foci shared truncal somatic mutations, indicating a common ancestral clone. However, additional mutations or copy number alterations restricted to the either component suggested divergent evolution at the genomic level. This was confirmed at the transcriptome level since while the urothelial component exhibited a basal-like subtype (TCGA2014: cluster III, LundTax: basal/squamous-like), the sarcomatoid morphology was predominantly cluster IV (claudin-low). Protein expression was consistent with a basal-like phenotype in both morphologies in 18/21 of cases. However, most cases had evidence of active epithelial-to-mesenchymal transition (E-Cad ↓ and Zeb1 or TWIST1 ↑) from urothelial toward the sarcomatoid morphology. Drug response signatures nominated different targets for each morphology and proposed agents under clinical investigation in liposarcoma or other sarcoma. PD-L1 expression was higher in the sarcomatoid than the urothelial component.
Conventional urothelial and adjacent sarcomatoid morphologies of MIBC arise from the same common ancestor and share a basal-like phenotype. However, divergence between the morphologies at the genome, transcriptome, and proteome level suggests differential sensitivity to therapy.
肌肉浸润性膀胱癌（MIBC）的肉瘤样形态与不良预后相关。然而，常规尿路上皮和同步肉瘤样形态之间的基因组、转录组和蛋白质组关系尚未明确。
我们收集了 21 例 MIBC 患者的肿瘤标本，这些患者的肿瘤焦点内同时存在常规尿路上皮和相邻的肉瘤样形态。我们进行了全面的病理和免疫组织化学特征分析，并在 4 例选定的病例中，对两种形态成分进行了靶向 DNA 测序和全转录组分析。
来自同一 MIBC 焦点的同步肉瘤样和尿路上皮形态具有共同的体细胞突变，表明存在共同的祖细胞克隆。然而，仅在某个成分中发现的额外突变或拷贝数改变表明在基因组水平上存在分化进化。这在转录组水平上得到了证实，因为尽管尿路上皮成分表现出基底样亚型（TCGA2014：cluster III，LundTax：基底/鳞状样），但肉瘤样形态主要是 cluster IV（claudin-low）。在 21 例病例中的 18 例中，两种形态的蛋白表达均与基底样表型一致。然而，大多数病例的尿路上皮向肉瘤样形态的上皮-间充质转化（E-Cad↓和 Zeb1 或 TWIST1↑）具有活性。药物反应特征为每种形态指定了不同的靶点，并提出了在脂肪肉瘤或其他肉瘤中进行临床研究的候选药物。PD-L1 在肉瘤样成分中的表达高于尿路上皮成分。
MIBC 的常规尿路上皮和相邻肉瘤样形态来自同一共同祖细胞，具有基底样表型。然而，在基因组、转录组和蛋白质组水平上的形态分化表明对治疗的敏感性存在差异。
