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尿路上皮肿瘤 luminal 型的分子病理学。

Molecular pathology of the luminal class of urothelial tumors.

机构信息

Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.

Division of Urological Research, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.

出版信息

J Pathol. 2019 Nov;249(3):308-318. doi: 10.1002/path.5318. Epub 2019 Aug 27.

Abstract

Molecular subtypes of urothelial carcinoma may be divided into luminal and nonluminal tumors. Nonluminal tumors are composed of cases with basal/squamous-like or small cell/neuroendocrine features, with a consensus on the molecular characteristics of the respective subtype. In contrast, luminal tumors are more disparate with three to five suggested subtypes and with definitions that do not always cohere. To resolve some of these disparities we assembled a cohort of 344 luminal tumors classified as urothelial-like (Uro), with the subtypes UroA, UroAp, UroB, and UroC, or genomically unstable (GU) according to the LundTax system. Cases were systematically analyzed by immunohistochemistry using antibodies for proteins representing important biological processes or cellular states: KRT5, EGFR, and CDH3 for the integrity of a basal cell layer; CCNB1, Ki67, and FOXM1 for proliferation; FGFR3 and ERBB2 for receptor tyrosine kinase status; CCND1, CDKN2A(p16), RB1, and E2F3 for cell cycle regulation; PPARG, GATA3, and TP63 for the differentiation regulatory system; and KRT20 and UPK3 for the differentiation readout. We show that Uro tumors form one, albeit heterogenous, group characterized by FGFR3, CCND1, and RB1 expression, but low or absence of CDKN2A(p16) and ERBB2 expression. The opposite expression pattern is observed in GU cases. Furthermore, Uro tumors are distinguished from GU tumors by showing a high RB1/p16 expression ratio. Class defining characteristics were independent of pathological stage and growth pattern, and thus intrinsic. In Uro tumors, proliferation was limited to a well-defined single layer of basal-like cells in UroA tumors but occurred throughout the tumor parenchyma, independent of the basal layer, in the more progressed UroAp and UroC tumors. A similar change in proliferation topology was not observed in GU. We conclude that luminal urothelial carcinomas consist, at the molecular pathology level, of two major subtypes, the larger heterogenous Uro and the biologically distinct GU subtype. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

摘要

尿路上皮癌的分子亚型可分为 luminal 型和非 luminal 型肿瘤。非 luminal 型肿瘤由具有基底/鳞状样或小细胞/神经内分泌特征的病例组成,对于各自亚型的分子特征有共识。相比之下,luminal 型肿瘤更为多样化,有三到五种建议的亚型,并且定义并不总是一致。为了解决其中的一些差异,我们收集了一组 344 例 luminal 型肿瘤,根据 LundTax 系统分类为尿路上皮样(Uro),亚类包括 UroA、UroAp、UroB 和 UroC,或基因组不稳定(GU)。通过免疫组织化学分析,使用代表重要生物学过程或细胞状态的蛋白质的抗体对病例进行系统分析:KRT5、EGFR 和 CDH3 用于基底细胞层的完整性;CCNB1、Ki67 和 FOXM1 用于增殖;FGFR3 和 ERBB2 用于受体酪氨酸激酶状态;CCND1、CDKN2A(p16)、RB1 和 E2F3 用于细胞周期调节;PPARG、GATA3 和 TP63 用于分化调节系统;以及 KRT20 和 UPK3 用于分化输出。我们表明,Uro 肿瘤形成一个单一的、异质的群体,其特征是 FGFR3、CCND1 和 RB1 的表达,但 CDKN2A(p16)和 ERBB2 的表达较低或缺失。GU 病例则表现出相反的表达模式。此外,Uro 肿瘤与 GU 肿瘤的区别在于 RB1/p16 表达比值高。分类特征独立于病理分期和生长模式,因此是内在的。在 Uro 肿瘤中,增殖仅限于 UroA 肿瘤中明确的单一基底样细胞层,但在更进展的 UroAp 和 UroC 肿瘤中,增殖发生在整个肿瘤实质中,与基底层无关。GU 中没有观察到类似的增殖拓扑变化。我们的结论是,在分子病理学水平上,尿路上皮癌主要由两个主要亚型组成,较大的异质 Uro 型和生物学上不同的 GU 型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d63/6851980/003cf70c7000/PATH-249-308-g001.jpg

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