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

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

doi:10.1038/s41467-019-10873-y

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

Nat Commun. 2019 Jul 5;10(1):2977. doi: 10.1038/s41467-019-10873-y.

Authors

Brian D Robinson^{1

2

3}, Panagiotis J Vlachostergios⁴, Bhavneet Bhinder^{5

6}, Weisi Liu⁴, Kailyn Li⁴, Tyler J Moss⁷, Rohan Bareja^{5

6}, Kyung Park¹, Peyman Tavassoli¹, Joanna Cyrta^{1

3}, Scott T Tagawa^{2

3

4

8}, David M Nanus^{2

3

4

8}, Himisha Beltran^{2

3

4

8}, Ana M Molina^{2

3

4

8}, Francesca Khani^{1

2

3}, Juan Miguel Mosquera^{1

2

3}, Evanguelos Xylinas^{2

9}, Shahrokh F Shariat^{2

10}, Douglas S Scherr², Mark A Rubin^{1

2

3

8

11}, Seth P Lerner¹², Surena F Matin¹³, Olivier Elemento^{3

5

6

8}, Bishoy M Faltas^{14

15

16

17}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
² Department of Urology, Weill Cornell Medicine, New York, NY, 10065, USA.
³ Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA.
⁴ Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, 10065, USA.
⁵ Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, 10065, USA.
⁶ Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, 10021, USA.
⁷ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁸ Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, 10065, USA.
⁹ Department of Urology, Cochin Hospital, APHP, Paris Descartes University, Paris, 75014, France.
¹⁰ Department of Urology, Medical University of Vienna, Vienna, 1190, Austria.
¹¹ Department of Biomedical Research, University of Bern, Bern, 3008, Switzerland.
¹² Scott Department of Urology, Baylor College of Medicine, Houston, TX, 77030, USA.
¹³ Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹⁴ Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA. bmf9003@med.cornell.edu.
¹⁵ Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, 10065, USA. bmf9003@med.cornell.edu.
¹⁶ Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, 10065, USA. bmf9003@med.cornell.edu.
¹⁷ Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, 10065, USA. bmf9003@med.cornell.edu.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Carcinoma, Transitional Cell / genetics
Carcinoma, Transitional Cell / immunology
Carcinoma, Transitional Cell / pathology*
DNA Mutational Analysis
Down-Regulation
Exome Sequencing
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Kidney Neoplasms / genetics
Kidney Neoplasms / immunology
Kidney Neoplasms / pathology*
Male
Microsatellite Instability
Middle Aged
Mutation
Receptor, Fibroblast Growth Factor, Type 3 / genetics
Receptor, Fibroblast Growth Factor, Type 3 / metabolism*
Sequence Analysis, RNA
Signal Transduction / genetics
T-Lymphocytes / immunology*
Tumor Microenvironment / immunology
Ureteral Neoplasms / genetics
Ureteral Neoplasms / immunology
Ureteral Neoplasms / pathology*
Urothelium / pathology

Substances

FGFR3 protein, human
Receptor, Fibroblast Growth Factor, Type 3