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.

Expression of the activating CD94/NKG2C killer lectin-like receptor (KLR) specific for HLA-E was analyzed in peripheral blood lymphocytes (PBLs) from healthy adult blood donors; the expression of other natural killer (NK) cell receptors (ie, CD94/NKG2A, KIR, CD85j, CD161, NKp46, NKp30, and NKG2D) was also studied. Human cytomegalovirus (HCMV) infection as well as the HLA-E and killer immunoglobulin-like receptor (KIR) genotypes were considered as potentially relevant variables associated with CD94/NKG2C expression. The proportion of NKG2C ؉ lymphocytes varied within a wide range (<0.1% to 22.1%), and a significant correlation (r ‫؍‬ 0.83; P < .001) between NKG2C ؉ NK and T cells was noticed. The HLA-E genotype and the number of activating KIR genes of the donors were not significantly related to the percentage of NKG2C ؉ lymphocytes. By contrast, a positive serology for HCMV, but not for other herpesviruses (ie, Epstein-Barr and herpes simplex), turned out to be strongly associated (P < specifically recognize HLA class I molecules and are expressed by natural killer and T-cell subsets. 1-4 Single cells 2 bear variable combinations of these natural killer cell receptors (NKRs), presumably resulting from stochastic gene activation/silencing events that take place during their maturation. 5 The diversity of NKRs observed in different individuals is in part genetically determined, because distinct KIR haplotypes include variable sets of genes. 1 On the other hand, there is evidence that microbial infections may also influence the NKR repertoire. In this regard, murine cytomegalovirus (MCMV) promotes an expansion of NK cells bearing the Ly49H receptor specific for the m157 viral glycoprotein, 6 which plays a crucial role in the immune response to infection. [7][8][9] Moreover, increased proportions of CD8 ϩ T cells with an effector/ memory phenotype bearing inhibitory NKRs (ie, CD94/NKG2A) have been observed in mice infected by different viruses 10-12 as well as in human immunodeficiency virus (HIV)-infected patients. 13 CD94, NKG2A, and NKG2C are C-type lectins encoded at the NK gene complex (NKC) in human chromosome 12. 14 Surface expression of NKG2A/C molecules requires their covalent assembly with CD94. 4,15,16 The CD94/NKG2A heterodimer constitutes an inhibitory receptor that recruits the protein tyrosine phosphatase containing SH2 domain-1 (SHP-1) through the immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing NKG2A subunit, whereas CD94/NKG2C is coupled to a tyrosine kinase activation pathway through the DAP12 adapter. 17,18 In human beings, both NKRs specifically recognize HLA-E, which presents peptides derived from the signal sequences of other HLA class I molecules [19][20][21][22] ; HLA-E allotypes contain either an Arg (HLA-E R107 ) or a Gly (HLA-E G107 ) at position 107. 23 The biologic relevance of such structural dimorphism remains unclear, but it may affect surface expression levels of the class Ib molecule 24,25 and its interaction with CD94/NKG2 receptors. 26 A number of studies have addre...

In the second article in the PROGRESS series on prognostic factor research, Sara Schroter and colleagues discuss the role of prognostic factors in current clinical practice, randomised trials, and developing new interventions, and explain why and how prognostic factor research should be improved.

Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.