Assessment of Luminal and Basal Phenotypes in Bladder Cancer

Charles C Guo,Guoliang Yang,Dan Theodorescu,Vipulkumar Dadhania,Miao Zhang,Marek Kimmel,David J Mcconkey,Colin P Dinney ,David Cogdell,Peng Wei,Sangkyou Lee,John N Weinstein,Hui Yao,Ziqiao Wang,Jianjun Gao,Jolanta Bondaruk,June Goo Lee ,Christopher J Logothetis ,Woonyoung Choi,Li Zhang,Bogdan Czerniak

doi:10.1038/s41598-020-66747-7

Abstract

Genomic profiling studies have demonstrated that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to frontline chemotherapy. We analyzed the mRNA expressions of signature luminal and basal genes in bladder cancer tumor samples from publicly available and MD Anderson Cancer Center cohorts. We developed a quantitative classifier referred to as basal to luminal transition (BLT) score which identified the molecular subtypes of bladder cancer with 80–94% sensitivity and 83–93% specificity. In order to facilitate molecular subtyping of bladder cancer in primary care centers, we analyzed the protein expressions of signature luminal (GATA3) and basal (KRT5/6) markers by immunohistochemistry, which identified molecular subtypes in over 80% of the cases. In conclusion, we provide a tool for assessment of molecular subtypes of bladder cancer in routine clinical practice.

Highlights

Genomic profiling studies have demonstrated that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to frontline chemotherapy
To evaluate the molecular subtypes of bladder cancer we initially analyzed the mRNA expression in the The Cancer Genome Atlas (TCGA) cohort (n = 408 cases) of invasive bladder cancers[11]
Our hierarchical clustering using signature luminal and basal markers revealed two major subtypes referred to as luminal and basal as well as a small subset of samples which were negative for both groups of markers. (Fig. 2A) The first cluster referred to as luminal (n = 212 cases) was characterized by the expression of markers such as KRT20, GATA3, FOXA1, XBP1, and CD24 which were associated with terminal urothelial differentiation

Summary

Introduction

Genomic profiling studies have demonstrated that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to frontline chemotherapy. Recent genomic investigations revealed that bladder cancer is characterized by complex molecular alterations, heavy mutational load, and frequent involvement of a unique subset of chromatin remodeling genes[10,11,12] They have shown that expression signatures can be linked to cancer progression, metastases, and survival[9,13,14,15,16]. The markers characteristic of these two major groups reflect the expression signature of normal basal and intermediate/luminal urothelial cell layers Most importantly these two subtypes show distinct clinical behaviors and responses to chemotherapy[18,22,28,29,30]. We aimed to develop a quantitative algorithm for the assessment of luminal and basal phenotypes in bladder cancer and validated a simple immunohistochemical classifier which can be used in routine pathology practice to identify the intrinsic molecular subtypes of bladder cancer in primary care centers

Objectives

Methods

Results

Conclusion