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

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.

Keywords: DNA alterations; Molecular subtypes; Muscle-invasive bladder cancer.

Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1

Comparison of subtype calls in TCGA’s final dataset. Each group used TCGA’s normalized RNA-seq data to assign TCGA’s tumors to the UNC, MD Anderson, or Lund subtypes. Published calls made by a group at The Broad Institute [22] and TCGA were also included for comparison. The top left panel provides a schematic overview of the relationships among the calls made by the five groups. The heat maps display the relative expression of the gene sets that characterize each group’s subtypes. The red and green colors correspond to high and low relative expression, respectively. GU = genomically unstable; MDA = MD Anderson; NA = not applicable; SCCL = squamous cell carcinoma like; TCGA = The Cancer Genome Atlas; UNC = University of North Carolina; uroA = urobasal A; uroB = urobasal B.

Fig. 2

Enrichment of significantly mutated genes and CNAs in the UNC subtypes. Alterations are grouped according to predicted enrichment in basal versus luminal tumors, and the results are displayed as percentages of tumors in each subtype that contained the indicated alteration. The CNAs correspond to chromosomal amplification unless specifically identified as deletions (“del”). Fisher’s exact test was used to determine differences between subtypes. CNA = copy number aberration; UNC = University of North Carolina. * p < 0.05 was considered significant.

Fig. 3

Enrichment of significantly mutated genes and CNAs in the MD Anderson subtypes. Alterations are grouped according to predicted enrichment in basal versus luminal tumors, and the results are displayed as percentages of tumors in each subtype that contained the indicated alteration. The CNAs correspond to chromosomal amplification unless specifically identified as deletions (“del”). Fisher’s exact test was used to determine differences between subtypes. CNA = copy number aberration; MDA = MD Anderson. * p < 0.05 was considered significant.

Fig. 4

Enrichment of significantly mutated genes and CNAs in the Lund subtypes. Alterations are grouped according to predicted enrichment in basal versus luminal tumors, and the results are displayed as percentages of tumors in each subtype that contained the indicated alteration. The CNAs correspond to chromosomal amplification unless specifically identified as deletions (“del”). Fisher’s exact test was used to determine differences between subtypes. CNA = copy number aberration; GU = genomically unstable; Infil = infiltrated; SCCL = squamous cell carcinoma like; uroA = urobasal A; uroB = urobasal B. * p < 0.05 was considered significant.