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Journal ArticleDOI

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

TL;DR: The 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.
About: This article is published in European Urology.The article was published on 2017-09-01 and is currently open access. It has received 176 citations till now.

Summary (3 min read)

1. Introduction

  • 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 (CNAs) that are thought to underlie their distinct progression patterns, and biological and clinical properties.

2. Evidence acquisition

  • The authors used the complete The Cancer Genome Atlas (TCGA) RNA-seq dataset and three different published classifiers developed by their groups to assign TCGA’s bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them (Supplementary material).
  • The authors 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.

3.1. Clinical issues in bladder cancer

  • Clinical experience and emerging genomic data support the idea that bladder cancers progress along two largely nonoverlapping tracks (‘‘papillary’’ and ‘‘nonpapillary’’) that pose distinct challenges for clinical management [1– 3].
  • A significant proportion of cases (15–20%) of NMIBCs progress to become muscle invasive [1,2].
  • Currently no reliable tools are available to identify them before they become life threatening.
  • Many high-grade papillary tumors ultimately become BCG unresponsive, so clinicians are then faced with the dilemma of whether to continue using a bladder-sparing regimen or to employ definitive surgery.
  • Overall, it is hoped that by understanding the molecular mechanisms that give rise to papillary and nonpapillary bladder cancers, it will be possible to develop methods to inform clinical decision making at every step of disease progression and management.

3.2. Intrinsic subtypes of cancer

  • The widespread use of genomics to investigate cancer heterogeneity is transforming their understanding of cancer biology.
  • Importantly, patients whose tumors belonged to one of the subtypes (‘‘germinal centerlike DLBCL’’) had better clinical outcomes than patients with the other (‘‘activated B-like DLBCL’’) [5].
  • Patients with basal-like or HER2-enriched breast tumors had poor clinical outcomes in the absence of systemic therapy, but many of them benefited greatly from neoadjuvant chemotherapy (NAC) [[7_TD$DIFF]8,9].
  • In contrast, SERMs produced no benefit in patients with basal-like or HER2enriched tumors [[9_TD$DIFF]11].
  • Subsequent studies identified molecular subtypes in head and neck squamous cell carcinomas (SCCs) [ [11_TD$DIFF] 3], glioblastomas [ [12_TD$DIFF] 4], and pancreatic cancers [[13_TD$DIFF] 5], and more recent studies are characterizing molecular subtypes that cut across cancer types [ [14_TD$DIFF] 6].

3.3. DNA alterations in bladder cancers

  • The recently completed TCGA MIBC (BLCA) project produced a comprehensive, open-access catalog of DNA alterations in a cohort of over 400 MIBCs.
  • The first TCGA ‘‘bladder cancer study’’ reported the results of a comprehensive integrated genomic analysis of131 tumors [[15_TD$DIFF] 7], and a recent review article provided an update on 238 tumors [[5_TD$DIFF]18].
  • These initial results were also incorporated into a pan-cancer analysis that compared the genomic features of 12 different types of cancers [[14_TD$DIFF] 6].
  • Finally, a recent paper reported the comprehensive transcriptional analysis of a cohort of 460 patients with NMIBC [[16_TD$DIFF] 9].
  • The key findings will now be summarized briefly.

3.3.1. Major drivers of mutagenesis

  • Cigarette smoking is an established risk factor for bladder cancer [2], and chronic exposure to cigarette smoke-like nitrosamines (ie, BBN) causes bladder cancer in rodents [[17_TD$DIFF]20].
  • Interestingly, a significant number of bladder cancers contained mutations in NFE2L2 (NRF2) and TXNIP [[5_TD$DIFF]18] genes, which encode proteins that inhibit the damaging effects of the reactive oxygen species that are produced in response to cigarette smoke carcinogens.
  • A more recent reanalysis of the original TCGA cohort identified a novel DNA mutational signature associated with inactivating mutations in the gene encoding the nucleotide excision repair protein, ERCC2, and established that these signatures were enriched in tumors from smokers [ [19_TD$DIFF]23].
  • Aside from being upregulated by infection, APOBEC3B activity can also be increased by chemical carcinogens, which promote APOBEC3B-mediated mutagenesis by inducing the formation of the single-strand DNA intermediates that are formed during DNA damage and repair [[20_TD$DIFF] 4].
  • Taken together, accumulating data suggest that APOBEC-mediated mutations may play a central causative role in driving bladder cancer genomic heterogeneity and disease progression.

3.3.2. Major targets of DNA alterations

  • Histone modifications play central roles in the regulation of gene expression, and whole exome sequencing studies revealed that mutations in chromatin-modifying enzymes were extremely common in bladder cancers [ [23_TD$DIFF] 7].
  • RB1 inactivation was also much more common in MIBCs as compared with that in NMIBCs [[5_TD$DIFF]18], and mutations in RB1 tended to be associated with mutations in TP53 [[5_TD$DIFF]18].
  • Dysregulation of other genes that promote cell cycle progression was also common in bladder cancers.
  • Alternative mechanisms include alterations in highorder chromatin organization and gene expression.
  • They also contained activating mutations, fusions, or amplification of genes encoding members of the epidermal growth factor receptor (EGFR) family [[15_TD$DIFF] 7], including the EGFR itself (about 10% of tumors), ERBB2 (about 10% of tumors), ERBB3 (about 10% tumors), and ERBB4 (about 6% of tumors).

3.4. Molecular subtypes of bladder cancer

  • The identification and validation of molecular subtypes in other malignancies provided the impetus to use transcriptome profiling to search for molecular subtypes in bladder cancers.
  • The initial results established that unsupervised analyses of gene expression could distinguish most NMIBCs from most MIBCs [ [46_TD$DIFF]58– [47_TD$DIFF]60].
  • The genes that distinguished the two clusters had previously been implicated in urothelial differentiation and overlapped substantially with the genes that distinguished the basal-like and luminal intrinsic subtypes of breast cancer, leading the UNC investigators to name their MIBC subtypes ‘‘basal like’’ and ‘‘luminal’’ [[57_TD$DIFF]68].
  • Parallel efforts attempted to reconcile the molecular subtypes identified by the groups using shared whole transcriptome datasets [ [59_TD$DIFF]69– [60_TD$DIFF]71].
  • In the phase II trial that led to Food and Drug Administration approval of the drug, patients whose tumors belonged to TCGA cluster II obtained somewhat more benefit than patients whose tumors belonged to the other subtypes, and patients with ‘‘papillary’’ (cluster I) tumors derived little benefit, if at all [ [65_TD$DIFF]75].

3.5. Genomic alterations in molecular subtypes of MIBC

  • Given past observations in the molecular subtypes in other cancers, it seemed likely that the molecular subtypes of bladder cancer would contain distinct mutations and CNAs.
  • The authors then examined each subtype for its content of specific DNA mutations (n = 391, available from Firehose [https://gdac. broadinstitute.org/]) and CNAs (n = 404, available from cBioportal [http://www.cbioportal.org/]).
  • Fisher’s exact test was used to determine differences arolina.
  • Consistent with the overall hypothesis, several of the alterations were significantly enriched in either UNC basal-like or luminal cancers (Fig. 2).
  • On the other hand, subdividing the UNC basal-like and luminal tumors into the other Lund subtypes yielded additional and highly informative patterns of mutation and CNA enrichment.

4. Conclusions

  • Molecular subtypes of bladder cancer are enriched with specific genetic alterations.
  • It is very interesting that the GU and uroA tumors are enriched with somewhat mutually exclusive patterns of mutations and CNAs involving key luminal genes (PPARG/GATA3 vs FGFR3).
  • It should be emphasized that their understanding of the biological and clinical properties of the molecular subtypes of bladder cancer is still fairly limited.
  • This information has important implications for prognostication and subtype-based therapy.
  • Analysis and interpretation of data: Choi, Ochoa, McConkey.

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Figures (3)
Citations
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Journal ArticleDOI
TL;DR: In this paper, a consensus set of six molecular classes (luminal papillary (24%), luminal nonspecified (8), luminal unstable (15), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%) was identified.

629 citations

Journal ArticleDOI
05 Apr 2018-Cell
TL;DR: A biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer and indicates that patient- derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.

477 citations


Cites background from "Genetic Alterations in the Molecula..."

  • ...It is conceivable that this phenotypic plasticitymay reflect a natural disease process in which progression of some bladder tumors is associated with luminal to basal subtype switching (Choi et al., 2017)....

    [...]

Journal ArticleDOI
TL;DR: Findings reveal high expression of the circular RNA circPRKCI drives lung adenocarcinoma tumorigenesis and may serve as a potential therapeutic target in patients with lungAdenocARCinoma.
Abstract: Somatic copy number variations (CNV) may drive cancer progression through both coding and noncoding transcripts. However, noncoding transcripts resulting from CNV are largely unknown, especially for circular RNAs. By integrating bioinformatics analyses of alerted circRNAs and focal CNV in lung adenocarcinoma, we identify a proto-oncogenic circular RNA (circPRKCI) from the 3q26.2 amplicon, one of the most frequent genomic aberrations in multiple cancers. circPRKCI was overexpressed in lung adenocarcinoma tissues, in part due to amplification of the 3q26.2 locus, and promoted proliferation and tumorigenesis of lung adenocarcinoma. circPRKCI functioned as a sponge for both miR-545 and miR-589 and abrogated their suppression of the protumorigenic transcription factor E2F7 Intratumor injection of cholesterol-conjugated siRNA specifically targeting circPRKCI inhibited tumor growth in a patient-derived lung adenocarcinoma xenograft model. In summary, circPRKCI is crucial for tumorigenesis and may serve as a potential therapeutic target in patients with lung adenocarcinoma.Significance: These findings reveal high expression of the circular RNA circPRKCI drives lung adenocarcinoma tumorigenesis. Cancer Res; 78(11); 2839-51. ©2018 AACR.

197 citations


Cites background from "Genetic Alterations in the Molecula..."

  • ...Taking epithelial cancers as an example, integrated cancer genomic 8 analysis and transgenic animal model have confirmed some well-known amplicons induced 9 proto-oncogenic proteins like MYC(7) and PIK3CA(8), as well as deletions induced tumor 10 suppressor like RB1(9) and PTEN(10)....

    [...]

Journal ArticleDOI
TL;DR: BLCA can be stratified into six molecular subtypes with different overall survival (OS) and molecular features, and molecular subtyping is a promising way to tailor disease management for those who will benefit most.

192 citations

Journal ArticleDOI
TL;DR: Current evidence for the management of conventional, variant and divergent urothelial cancer subtypes, as well as non-urothelial bladder cancers, are presented, and how the integration of genomic, transcriptomic and proteomic characterization of bladder cancer could guide future therapies are discussed.
Abstract: Bladder cancer is a heterogeneous group of tumours with at least 40 histological subgroups. Patients with localized disease can be cured with surgical resection or radiotherapy, but such curative options are limited in the setting of recurrent disease or distant spread, in which case systemic therapy is used to control disease and palliate symptoms. Cytotoxic chemotherapy has been the mainstay of treatment for advanced bladder cancer, but high-quality evidence is lacking to inform the management of rare subgroups that are often excluded from studies. Advances in molecular pathology, the development of targeted therapies and the resurgence of immunotherapy have led to the reclassification of bladder cancer subgroups and rigorous efforts to define predictive biomarkers for cancer therapies. In this Review, we present the current evidence for the management of conventional, variant and divergent urothelial cancer subtypes, as well as non-urothelial bladder cancers, and discuss how the integration of genomic, transcriptomic and proteomic characterization of bladder cancer could guide future therapies.

112 citations

References
More filters
Journal ArticleDOI
17 Aug 2000-Nature
TL;DR: Variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals were characterized using complementary DNA microarrays representing 8,102 human genes, providing a distinctive molecular portrait of each tumour.
Abstract: Human breast tumours are diverse in their natural history and in their responsiveness to treatments. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce information from the cell's identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, using complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific features of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.

14,768 citations


"Genetic Alterations in the Molecula..." refers background in this paper

  • ...Parallel studies in breast cancer revealed that they could also be grouped into ‘‘intrinsic subtypes’’ that had very different biological properties and behaved clinically as distinct disease entities [6,7]....

    [...]

Journal ArticleDOI
15 Oct 1999-Science
TL;DR: A generic approach to cancer classification based on gene expression monitoring by DNA microarrays is described and applied to human acute leukemias as a test case and suggests a general strategy for discovering and predicting cancer classes for other types of cancer, independent of previous biological knowledge.
Abstract: Although cancer classification has improved over the past 30 years, there has been no general approach for identifying new cancer classes (class discovery) or for assigning tumors to known classes (class prediction). Here, a generic approach to cancer classification based on gene expression monitoring by DNA microarrays is described and applied to human acute leukemias as a test case. A class discovery procedure automatically discovered the distinction between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) without previous knowledge of these classes. An automatically derived class predictor was able to determine the class of new leukemia cases. The results demonstrate the feasibility of cancer classification based solely on gene expression monitoring and suggest a general strategy for discovering and predicting cancer classes for other types of cancer, independent of previous biological knowledge.

12,530 citations


"Genetic Alterations in the Molecula..." refers result in this paper

  • ...A pioneering study in leukemia demonstrated that mRNA expression profiling could be used to distinguish ALL from AML with a high degree of accuracy [4], and a subsequent study used gene expression profiling to identify two previously unrecognized molecular subtypes of diffuse large B-cell lymphoma [5]....

    [...]

Journal ArticleDOI
TL;DR: Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.
Abstract: The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.

10,791 citations


"Genetic Alterations in the Molecula..." refers background or result in this paper

  • ...Parallel studies in breast cancer revealed that they could also be grouped into ‘‘intrinsic subtypes’’ that had very different biological properties and behaved clinically as distinct disease entities [6,7]....

    [...]

  • ...Similar to basal-like breast cancers [7], the Lund SCCL and uroB tumors and the squamous/basal tumors identified by the groups at UNC, MD Anderson Cancer Center, and TCGA were aggressive, and associated with advanced stage and metastatic disease at presentation, squamous histopathological features, and shorter survival in the absence of neoadjuvant cisplatin-based combination chemotherapy [17,65,67,68,72]....

    [...]

Journal ArticleDOI
TL;DR: The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression, a higher rate of objective response, a longer duration of response, and a lower rate of death at 1 year.
Abstract: Background The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. Methods We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide with (143 women) or without trastuzumab (138 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). Results The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 ...

10,532 citations


"Genetic Alterations in the Molecula..." refers background in this paper

  • ...Patients with HER2-enriched tumors also obtained significant clinical benefit from ERBB2 antagonists [10]....

    [...]

Journal ArticleDOI
03 Feb 2000-Nature
TL;DR: It is shown that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour.
Abstract: 12 Pathology and Microbiology, and 13 Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.

9,493 citations


"Genetic Alterations in the Molecula..." refers background or result in this paper

  • ...Importantly, patients whose tumors belonged to one of the subtypes (‘‘germinal centerlike DLBCL’’) had better clinical outcomes than patients with the other (‘‘activated B-like DLBCL’’) [5]....

    [...]

  • ...A pioneering study in leukemia demonstrated that mRNA expression profiling could be used to distinguish ALL from AML with a high degree of accuracy [4], and a subsequent study used gene expression profiling to identify two previously unrecognized molecular subtypes of diffuse large B-cell lymphoma [5]....

    [...]

Related Papers (5)
Frequently Asked Questions (17)
Q1. What are the contributions in "Genetic alterations in the molecular subtypes of bladder cancer: illustration in the cancer genome atlas dataset" ?

In this paper, the authors showed that the uroA and uroB tumors are enriched with specific genetic alterations. 

Biological effects of these alterations will need to be explored in future functional studies. The precise mechanisms that cause them to appear more ‘ ‘ basal ’ ’ ( at the molecular level, and also in terms of their enrichment with squamous histological features and lethality ) will be very interesting ; their relatively high content of RB1 and NFE2L2 mutations suggests possible mechanisms. The existence of uroB tumors also suggests that basal versus luminal subtype class ‘ ‘ switching ’ ’ is possible. Clinically, it will be interesting to determine whether the uroA and uroB tumors are equally sensitive to FGFR inhibitors. 

Amplification of cyclin D1 was reported in approximately 20% of NMIBCs and MIBCs [1], and amplification of E2F3 was observed in high-grade T1 lesions and MIBCs [[29_TD$DIFF]1,32]. 

TP53 mutation frequencies and/or genomic instability to the formation of these two major gene expression subtypes [[52_TD$DIFF] 8]. 

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 most prevalent were inactivating mutations in ERCC2 (12% of tumors) [ [5_TD$DIFF]18], which were linked to sensitivity to neoadjuvant cisplatin-based combination chemotherapy [ [32_TD$DIFF] 5]. 

papillary NMIBCs are rarely lethal but recur almost always, necessitating that patients receive lifelong surveillance; the repeated surgical procedures required to deal with recurrences cause significant anxiety, discomfort, and morbidity, making bladder cancer the most expensive tumor on a per patient basis. 

NMIBCs are prone to recurrence, and it will be important to perform longitudinal studies to determine how often subtype membership is maintained in these recurrences. 

Although the biological consequences of these events have not been defined experimentally, they would be expected to lead to decreased RNA polymerase accessibility, gene silencing, and a less well-differentiated phenotype. 

Although the molecular mechanisms that underlie the benefit produced by chemotherapy in basal tumors are still under investigation, basal human bladder cancer cell lines are more sensitive to cisplatininduced apoptosis than are luminal cell lines (A. Ochoa, D.J. McConkey, unpublished observations). 

even though TCGA cluster IV tumors are heavily infiltrated with lymphocytes, the T cells appear to be more actively suppressed than are the T cells in the tumors that belong to TCGA cluster II luminal subtype [[66_TD$DIFF]76], which could explain why cluster IV tumors are somewhat less sensitive to immune checkpoint blockade. 

Although they cluster together with the squamous/basal tumors in the UNC, MD Anderson, and TCGA classifications, the genetic alterations in the uroB tumors more closely resemble those present in the luminal uroA subtype, supporting the conclusion that they represent progressed versions of the uroA cancers. 

Among the APOBEC genes, APOBEC3B appears to be most commonly overexpressed in solidtumors, and bladder cancers stand out for expressing some of the highest levels of APOBEC3B among all solid malignancies [[20_TD$DIFF] 4]. 

In the phase II trial that led to Food and Drug Administration approval of the drug, patients whose tumors belonged to TCGA cluster II obtained somewhat more benefit than patients whose tumors belonged to the other subtypes, and patients with ‘‘papillary’’ (cluster I) tumors derived little benefit, if at all [ [65_TD$DIFF]75]. 

In addition, as noted above, the uroB subtype may establish a precedent for luminal-to-basal subtype ‘‘switching’’ in bladder cancer. 

Included among them were alterations that were enriched in the breast cancer intrinsic subtypes (TP53, RB1, ERBB2, and PIK3CA), genes that displayed different mutation frequencies in NMIBCs versus MIBCs (FGFR3, KDM6A, and STAG2), and genes that encode for mRNAs that were enriched in basal or luminal MIBCs (EGFR, PPARG, GATA3, ELF3, and ERBB3). 

Given past observations in the molecular subtypes in other cancers, it seemed likely that the molecular subtypes of bladder cancer would contain distinct mutations and CNAs.