Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset.

Woonyoung Choi, Andrea Ochoa, David J McConkey, Mattias Aine, Mattias Höglund, William Y Kim, Francisco X Real, Anne E Kiltie, Ian Milsom, Lars Dyrskjøt, Seth P Lerner

Journal: European urology 2018;72(3):354-365

PMID: 28365159

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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 enriched with specific mutations 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 determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes.

EVIDENCE

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 aberrations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer.

Address: 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.; 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. Electronic address: [email protected].; 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 Ciències 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.

DOI: 10.1016/j.eururo.2017.03.010