A validation and extended description of the Lund taxonomy for urothelial carcinoma using the TCGA cohort

Abstract

Global gene expression analysis has been a major tool for urothelial carcinoma subtype discovery. This approach has revealed extensive complexity both in intrinsic features of the tumor cells and in the microenvironment. However, global gene expression cannot distinguish between gene expression signals originating from the tumor cells proper and from normal cells in the biopsy. Here, we use a large cohort of advanced urothelial carcinomas for which both gene expression data and extensive immunohistochemistry are available to create a supervised mRNA expression centroid classifier. This classifier identifies the major Lund taxonomy tumor cell phenotypes as defined by IHC. We apply this classifier to the independent TCGA dataset and show excellent associations between identified subtypes and genomic features. We validate a progressed version of Urothelial-like A (UroA-Prog) that shows FGFR3 mutations and CDKN2A deletions, and we show that the variant Urothelial-like C is almost devoid of FGFR3 mutations. We show that Genomically Unstable tumors are very distinct from Urothelial-like tumors at the genomic level, and that tumors classified as Basal/SCC-like all complied with the established definition for Basal/SCC-like tumors. We identify the Mesenchymal-like and Small-cell/Neuroendocrine-like subtypes, and demonstrate that patients with UroB and Sc/NE-like tumors show the worst overall survival.

Molecular pathology of the luminal class of urothelial tumors

“…Apart from frequently loss of KRT5 positive cells and frequent ERBB2 expression, the most distinct difference from the Uro was the inactivation of RB1 and increased expression of CDKN2A(p16). These findings are in line with the frequent genomic alterations of RB1 and almost absence of CDKN2A deletions in the GU subtype . In these aspects GU is very similar to carcinoma in situ of the bladder .…”

“…In addition, both show low expression of CDKN2A(p16) and ERBB2. The high expression of FGFR3 and low expression of CDKN2A is in accordance with the frequent activating mutations in FGFR3 and homozygous deletions of CDKN2A in this subtype [8]. The major differences are seen at the level of proliferation, growth pattern, and pathological grade.…”

“…UroB differs from UroA by regularly showing an increased number of cells expressing basal markers, and lower expression of the differentiation factors PPARG and GATA3. In this respect, UroB tumors develop towards a basal/squamous‐like phenotype, however, they do not conform to the consensus Ba/Sq definition . In addition, UroB cannot be the major progenitor of Ba/Sq tumors as UroB shows FGFR3 mutations in 50% of the cases whereas the Ba/Sq tumors rarely present with FGFR3 mutations .…”

“…In this respect, UroB tumors develop towards a basal/squamous‐like phenotype, however, they do not conform to the consensus Ba/Sq definition . In addition, UroB cannot be the major progenitor of Ba/Sq tumors as UroB shows FGFR3 mutations in 50% of the cases whereas the Ba/Sq tumors rarely present with FGFR3 mutations . Hence, UroB is a Uro tumor that has acquired some of the molecular features of basal/squamous tumors.…”

Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

“…12 NPS1 was rich in several basal markers, in lamina propria components, and presented with low levels of proteins that facilitate cell-basal membrane and cell-cell attachment, possibly indicating increased cell motility. Additionally, these tumors expressed at high levels proteins of the cell cycle progression, MYC and E2F transcriptional targets, all being features of aggressive BC, 12,13 also reflected at the higher proximity of the NPS1 profile to the MIBC proteome (Fig. 2b).…”