Discovery and characterization of molecular subtypes in high-grade urothelial carcinoma.

摘要

Bladder Cancer is the 4th most commonly diagnosed cancer in men and the 8th most deadly. Invasive bladder cancer (≥T2) has a 5 year survival rate of ~50% with the number decreasing to 15% for non organ confined disease. Multiple groups have performed molecular characterization of bladder tumors in an effort to identify bladder cancer subtypes. These groups have been able to effectively differentiate non-muscle invasive disease (low-grade) from muscle invasive (high-grade); since pathologists can reliably identify LG and HG tumors, molecular signatures of these two groups are not clinically useful. 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 high-grade, muscle invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer: "luminal" and "basal-like" that 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. Prediction analysis of microarrays (PAM) defined a gene set predictor: Bladder cancer Analysis of Subtypes by Expression (BASE47) that accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer. As an appreciation of subtype heterogeneity has revolutionized the care of breast cancer, these results also suggest stratification for therapy is indicated in bladder cancer as well.