Biological determinants of bladder cancer gene expression subtypes

Molecular stratification of tumors by gene expression profiling has been applied to a large number of human malignancies and holds great promise for personalized treatment. Comprehensive classification schemes for urothelial carcinoma have been proposed by three separate groups but have not previously been evaluated simultaneously in independent data. Here we map the interrelations between the proposed molecular subtypes onto the intrinsic structure of a rich independent dataset and show that subtype stratification within each scheme can be explained in terms of a set of common underlying biological processes. We highlight novel biological and genomic drivers of urothelial carcinoma molecular subtypes and show that tumors carrying genomic aberrations characteristic of distinct molecular pathways converge on a common top level phenotype corresponding to the two major molecular subtypes of non-muscle invasive disease.