Abstract IA03: Molecular subtypes of bladder cancer: Toward a more granular description of cancer heterogeneity
Authors: McConkey David J. , Choi Woonyoung , Dinney Colin P.N. , Siefker-Radtke Arlene , Czerniak Bogdan 
Published: August 2020

Abstract
Whole-transcriptome mRNA expression profiling studies have established that muscle-invasive bladder cancers (MIBCs) can be subdivided into “basal/squamous” and “luminal” molecular subtypes that are associated with distinct biologic and clinical properties. In general, basal/squamous tumors tend to be more highly enriched in canonical cancer stem cell and epithelial-to-mesenchymal transition (EMT) biomarkers, and perhaps as a consequence, they are associated with advanced stage and metastatic disease at presentation. On the other hand, luminal tumors are enriched with breast cancer luminal biomarkers, peroxisome proliferator activator receptor (PPARG) expression and pathway activation, members of the miR-200 family of EMT repressors, and activating mutations and fusions targeting fibroblast growth factor receptor-3 (FGFR3). Past studies demonstrated that subsets of both basal and luminal MIBCs respond to neoadjuvant chemotherapy as measured by downstaging to &lt;pT2 at cystectomy, although clinical benefit is greatest in patients with basal tumors, perhaps because they are associated with more subclinical metastatic disease. Completed phase II clinical trials employing small-molecule FGFR inhibitors have confirmed that some patients whose tumors contain activating mutations in FGFR3 obtain clinical benefit, confirming that FGFR3 is a viable target in luminal tumors.
As the available datasets grow larger, it has become possible to further subdivide the basal/squamous and luminal tumors into additional molecular subtypes. A fraction of basal/squamous tumors lose expression of basal keratins, TP63, and E- and P-cadherins and exhibit molecular features of “complete” EMT. These tumors are similar to claudin-low breast cancers and appear to be more aggressive, exemplified in the observation that patients with claudin-low tumors fail to benefit from neoadjuvant chemotherapy. It appears likely that sarcomatoid tumors represent a phenotypic conversion to the extreme end of the EMT spectrum. Likewise, neuroendocrine and small cell bladder cancers also appear to evolve from basal/squamous tumors via mechanisms that involve combined inactivation of TP53 and RB1.
Although the general determinants of basal/squamous molecular heterogeneity appear relatively straightforward, the extent of the heterogeneity that exists in luminal tumors is still emerging. The Lund group's overall dichotemization of luminal tumors into “genomically unstable” and “urothelial” is extremely attractive, but the determinants of heterogeneity within the urothelial tumors await definition. TCGA and the molecular subtypes consensus group identified a small but clinically aggressive luminal subtype that seems somewhat similar to carcinoma in situ (CIS), but precisely how it corresponds to the other luminal subtypes is also unclear. Finally, micropapillary tumors are enriched in luminal biomarkers and overexpression of ERBB2, but their biologic determinants are also unknown. Because non-muscle invasive bladder cancers (NMIBCs) are highly enriched with luminal tumors, it seems likely that the luminal subtypes will become more granular as larger NMIBC datasets are merged with the MIBCs.
Citation Format: David J. McConkey, Woonyoung Choi, Colin P.N. Dinney, Arlene Siefker-Radtke, Bogdan Czerniak. Molecular subtypes of bladder cancer: Toward a more granular description of cancer heterogeneity [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA03.