Molecular pathology of the luminal class of urothelial tumors

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.

An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer

“…All CK5/6 positive tumors were concurrently GATA3 positive and thereby not basal/squamous by definition 43 . Similar coexpression of basal- and luminal-like markers has been observed previously in the Urothelial-like B tumors 44 . The fraction of CK5/6 positive cells was associated with transcriptomic classes, with class 3 having the strongest enrichment for CK5/6 expression ( p = 4.5 × 10 −8 ; chi-squared test; Fig.…”

An integrated multi-omics analysis identifies clinically relevant molecular subtypes of non-muscle-invasive bladder cancer

“…All CK5/6 positive tumors were concurrently GATA3 positive and thereby not basal/squamous by definition 37 . Similar coexpression of basal- and luminal-like markers has been observed previously in the Urothelial-like B tumors 38 . The fraction of CK5/6 positive cells was strongly associated with transcriptomic classes, with class 3 having the strongest enrichment for CK5/6 expression (p=4.5 × 10 −8 ; Fig 4F ).…”

TP63 links chromatin remodeling and enhancer reprogramming to epidermal differentiation and squamous cell carcinoma development

“…Squamous cell carcinomas (SCCs) are a series of aggressive malignancies from various tissue origins, including the skin, head and neck, lung, and esophagus [ 1 , 2 ]. Squamous subtype cancers can also be identified in subsets of pancreatic [ 3 – 5 ], urothelial [ 6 ], and prostate cancer [ 7 ]. SCCs from various organs share some similar features, including their genomic landscapes, morphological characteristics, and molecular alterations [ 2 , 8 ].…”