EURURO Vol. 72 No. 3

Platinum Priority – Review – Urothelial Cancer

Editorial by Peter C. Black on pp. 366–367 of this issue

Genetic Alterations in the Molecular Subtypes of Bladder Cancer:

Illustration in the Cancer Genome Atlas Dataset

Woonyoung Choi

a , b ,

Andrea Ochoa

a , b ,

David J. McConkey

a , b , * ,

Mattias Aine

c ,

Mattias Ho¨glund

c ,

William Y. Kim

d ,

Francisco X. Real

e , f ,

Anne E. Kiltie

g ,

Ian Milsom

h ,

Lars Dyrskjøt

i ,

Seth P. Lerner

Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, Texas, USA;

Department of Cancer Biology, U.T. M.D. Anderson Cancer Center,

Houston, Texas, USA;

Division of Oncology and Pathology, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden;

University

of North Carolina, Chapel Hill, North Carolina, USA;

Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain;

Departament de Cie`ncies Experimentalsi de la Salut, Universitat Pompeu Fabra, Barcelona, Spain;

Department of Oncology, University of Oxford, Oxford,

UK;

Institute of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden;

Department of Molecular Medicine, Aarhus

University Hospital, Aarhus, Denmark;

TCGA Analysis Working Group, Baylor College of Medicine, Houston, Texas, USA

E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 3 5 4 – 3 6 5

available at

www.scienced irect.com

journal homepage:

www.europeanurology.com

Article info

Article history:

Accepted March 6, 2017

Associate Editor:

James Catto

Keywords:

Molecular subtypes

Muscle-invasive bladder cancer

DNA alterations

Abstract

Context:

Recent whole genome mRNA expression profiling studies revealed that bladder

cancers can be grouped into molecular subtypes, some of which share clinical properties

and gene expression patterns with the intrinsic subtypes of breast cancer and the

molecular subtypes found in other solid tumors. The molecular subtypes in other solid

tumors are enrichedwith specificmutations and copy number aberrations that are thought

to underlie their distinct progression patterns, and biological and clinical properties.

Objective:

The availability of comprehensive genomic data from The Cancer Genome

Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA

alterations with tumor molecular subtype membership. Our overall goal was to deter-

mine whether specific DNA mutations and/or copy number variations are enriched in

specific molecular subtypes.

Evidence:

[1_TD$DIFF]

We used the complete TCGA RNA-seq dataset and three different published

classifiers developed by our groups to assign TCGA’s bladder cancers to molecular

subtypes, and examined the prevalence of the most common DNA alterations within

them. We interpreted the results against the background of what was known from the

published literature about the prevalence of these alterations in nonmuscle-invasive

and muscle-invasive bladder cancers.

Evidence synthesis:

The results confirmed that alterations involving

RB1

and

NFE2L2

were enriched in basal cancers, whereas alterations involving

FGFR3

and

KDM6A

were

enriched in luminal tumors.

Conclusions:

The results further reinforce the conclusion that the molecular subtypes of

bladder cancer are distinct disease entities with specific genetic alterations.

Patient summary:

Our observation showed that some of subtype-enriched mutations

and copy number

[6_TD$DIFF]

aberrations are clinically actionable, which has direct implications for

the clinical management of patients with bladder cancer.

* Corresponding author. Johns Hopkins Greenberg Bladder Cancer Institute, 600 Wolfe Street,

Marburg 149, Baltimore, MD 21287-2101, USA.

E-mail address:

djmcconkey@jhmi.edu

(D.J. McConkey).

http://dx.doi.org/10.1016/j.eururo.2017.03.010

0302-2838/