Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology

Abstract

We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of highgrade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed "luminal" and "basal-like," which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtypespecific therapies, will be of interest.I n the United States, urothelial carcinoma (UC) of the bladder is the fourth most common malignancy in men and the ninth most common in women, with 72,570 new cases and 15,210 deaths expected in 2013 (1). Bladder cancer is heterogeneous and can be histologically divided into low-grade and high-grade disease. Whereas low-grade tumors are almost invariably noninvasive (Ta), high-grade tumors can be classified based on invasion into the muscularis propria of the bladder, as non-muscle invasive bladder cancer (NMIBC; Tis, Ta, T1) or muscle invasive bladder cancer (MIBC; ≥T2). Low-grade tumors are associated with a high rate of recurrence but an excellent overall prognosis, with a 5-y survival in the range of 90%. In contrast, high-grade MIBC has a relatively poor 5-y overall survival, 68% for T2 and decreasing to 15% for non-organ-confined disease (i.e., pT3 and pT4) (1, 2).Along with divergent pathologies and prognosis, low-grade and high-grade UCs are associated with distinct genetic alterations. For example, low-grade UCs are enriched for activating mutations in fibroblast growth factor 3 (FGFR3), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and inactivating lysine (K)-specific demethylase 6A (KDM6A) mutations, whereas high-grade, muscle-invasive tumors are enriched for tumor protein p53 (TP53) and retinoblastoma 1 (RB1) pathway alterations (3-10).Several reports have examined the gene expression profiles of primary bladder tumors. From these studies, it is apparent that low-grade noninvasive and high-grade muscle-invasive tumors harbor distinct gene expression patterns, and that further molecular subsets can be identified within low-grade and high-grade tumors (5,(11)(12)(13)(14). Moreover, a number of gene signatures have been developed that can predict tumor stage, lymph node metastases, and bladder cancer progression (11-13, 15-18). There are established gene expression patterns that differentiate lowgrade and high-grade tumors;...

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

“…It is almost never associated with human papillomavirus infection, with the rare exception of some cases with a basaloid morphology [67,68]. Interestingly, recent genomic data have described a basal/squamous-like molecular subtype that has squamoid morphology and immunophenotype and is associated with poor survival and poor response to systemic therapy [69,70]. Glandular neoplasms constitute the second most common form of divergent differentiation, seen in up to 18% of invasive tumours and defined by the presence of gland formation [71][72][73].…”

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

“…Studies of TP63 isoforms show that Np63 expression is linked to EMT in tumours 169 and this is associated with a more 'basal' phenotype with adverse prognosis [169][170][171] . Recent expression profiling of large numbers of MIBC defines a claudin-low basal subtype (discussed below) that is characterised by the enrichment of EMT markers and the expression of low levels of cytokeratins 37,172 .…”

“…Three subsequent studies of MIBC have defined transcriptional subtypes 37, 172,193 . There is considerable overlap in these subtypes 194 195 .…”

Not all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy

“…The recent molecular characterization of muscle invasive bladder cancer and the classification into luminal and basal subtypes has provided a framework that promises to facilitate the development of novel therapeutics in muscle invasive bladder cancer (1)(2)(3)(4)(5). In this context we have focused on NOTCH signaling as critical pathway in bladder cancer.…”