A Consensus Molecular Classification of Muscle-invasive Bladder Cancer

Abstract

Background: Muscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application. Objective: To achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes. Design, setting, and participants: We used 1750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts. Outcome measurements and statistical analysis: We performed a network-based analysis of six independent MIBC classification systems to identify a consensus set of molecular classes. Association with survival was assessed using multivariable Cox models. Results and limitations: We report the results of an international effort to reach a consensus on MIBC molecular subtypes. We identified a consensus set of six molecular classes: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes. We provide a single-sample classifier that assigns a consensus class label to a tumor sample’s transcriptome. Limitations of the work are retrospective clinical data collection and a lack of complete information regarding patient treatment. Conclusions: This consensus system offers a robust framework that will enable testing and validation of predictive biomarkers in future prospective clinical trials. Patient summary: Bladder cancers are heterogeneous at the molecular level, and scientists have proposed several classifications into sets of molecular classes. While these classifications may be useful to stratify patients for prognosis or response to treatment, a consensus classification would facilitate the clinical use of molecular classes. Conducted by multidisciplinary expert teams in the field, this study proposes such a consensus and provides a tool for applying the consensus classification in the clinical setting.

Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma

“…The vast majority (IHC: 92% and mRNA: 87%) of this cohort was classified as "luminal-like" subtypes Uro or GU, which in more advanced stages make up only about 50%. 28,30,44 The dynamics of molecular subtypes in the cohort was interesting: Patients that progressed with the Uro subtype tended to have only prior Uro tumors; patients that progressed with the GU subtype, tended to have either Uro or GU prior tumors; and patient that progressed with nonluminal subtypes had few prior tumors that could be of any subtype. These data explain to some degree why certain subtypes are more frequent at different disease stages.…”

“…The consensus molecular subtypes of MIBC were also applied. 30 Molecular classification results are available in Supporting Information Table S1.…”

Predictive biomarkers for drug response in bladder cancer

“…1); but since then, one has been developed and will be reported soon. 30 However, meta-analyses showed that the different subtyping methods all shared dichotomization "basal" and "luminal" at the highest level. 31,32 Furthermore, the basal subtype was always characterized by high expression of KRT5/6 and KRT14, and low/undetectable expression of FOXA1 and GATA3, whereas the luminal subtypes were enriched with biomarkers characteristic of urothelial differentiation.…”

Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

“…6 Recently, a consensus was reached for the molecular classification of MIBC identifying six subtypes with distinct histological, molecular and clinical characteristics. 7 Molecular subtypes of the NMIBC are less studied. Classification of NMIBC based on RNA-sequencing 8 supports the existence of three subclasses, including a luminal/well-differentiated (Class 1), a basal-like (Class 3) and a luminal/carcinoma in situ (CIS)-like subtype (Class 2), the latter associated with worse outcome in comparison to the two former (UROMOL cohort).…”