Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling

Brian D Robinson,Kyung Park,Ana M Molina,David M Nanus,Douglas S Scherr,Kailyn Li,Shahrokh F Shariat,Peyman Tavassoli,Scott T Tagawa,Mark A Rubin,Weisi Liu,Rohan Bareja,Himisha Beltran,Joanna Cyrta,Olivier Elemento,Juan Miguel Mosquera,Bhavneet Bhinder,Seth P Lerner,Évanguelos Xylinas ,Francesca Khani,Surena F Matin,Tyler J Moss,Panagiotis J Vlachostergios,Bishoy Faltas

doi:10.1038/s41467-019-10873-y

Abstract

Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies.

Highlights

Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype
We identified FGFR3 mutations in 11/37 (29.7%) (Fig. 1a), a significantly higher frequency compared to the 17/124 (13.7%) mutations detected in the Cancer Genome Atlas (TCGA) urothelial carcinoma of the bladder (UCB) (Wilcoxon test P = 0.04) (Fig. 1b)
Our study revealed a lower total mutational burden (TMB) in non-Lynch syndrome UTUC compared to UCB

Summary

Introduction

Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. We report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. To dissect the central biological features of UTUC’s tumor and immune cell compartments, we analyzed whole-exome sequencing (WES) and RNA sequencing (RNAseq) data from high-grade UTUC tumors from patients at three different institutions [Weill Cornell Medicine (WCM), Baylor College of Medicine and MD Anderson Cancer Center (BCM–MDACC)]. We used whole-exome and RNAseq data from UCB tumors from the TCGA cohort as a comparison cohort[5] This enabled us to define the biological differences between UC arising from the upper and lower urinary tracts and to gain insights into the unique mechanisms that drive UTUC biology. We report that the tumor mutational burden in sporadic UTUC is lower than UCB, despite reduced expression of DNA mismatch repair (MMR) transcripts and proteins

Methods

Results

Conclusion