Intratumoral Heterogeneity of Bladder Cancer by Molecular Subtypes and Histologic Variants

Warrick, Joshua I.; Sjödahl, Gottfrid; Kaag, Matthew; Raman, Jay D.; Merrill, Suzanne; Shuman, Lauren; Chen, Guoli; Walter, Vonn; DeGraff, David J.

doi:10.1016/j.eururo.2018.09.003

Cited by 181 publications

(181 citation statements)

References 10 publications

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“…Furthermore, we observed little evidence of intra-tumor heterogeneity in molecular subtype markers. This is in contrast to recently published work suggesting that some tumors exhibit a high degree of intra-tumoral heterogeneity (35,36). However, we note this difference may be due to definitions of subtype applied, the profiling strategy of this and other studies, and the small numbers of samples tested in each study.…”

Section: Discussioncontrasting

confidence: 99%

Defining the microenvironment landscape of bladder cancer using highly multiplexed spatial genomic and proteomic analysis

Reeves

Zhang²,

Norgaard

et al. 2019

Preprint

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One Sentence Summary:A new method for capturing tumor-immune signaling in FFPE tissues explores how the PPARG signaling axis is associated with immune cell exclusion in bladder cancer. Abstract:Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. PD-1 pathway targeting immunotherapies have been approved to treat advanced bladder cancer, but most patients exhibit primary resistance, suggesting that immune evasion mechanisms exist. The PPARγ pathway has been identified as a potential therapeutic target in MIBC that is associated with reduced CD8+ T-cell infiltration and increased resistance to immunotherapies. We comprehensively profiled the tumor microenvironment (TME) in formalin-fixed, paraffin-embedded (FFPE) tissues from a cohort of PPARγ high (n=13) and PPRARγ low (n=12) MIBC, integrating bulk gene expression, targeted mutation sequencing, immunohistochemistry and multiplex spatial profiling of RNA and protein expression on the GeoMx™ Digital Spatial Profiling (DSP) platform. Molecular subtyping was consistent between traditional methods and GeoMx profiling, and, in this cohort, we observed little evidence of spatial heterogeneity in tumor subtyping. The previously characterized T-cell exclusion phenotype of PPARγ high MIBC was recapitulated on the GeoMx platform and was further extended to show that this is a general phenomenon across immune cell types, supporting potential combination of PPARγ inhibition with ICIs. Furthermore, we found that while immune cells were excluded from PPARγ high tumors, the stromal compartment from these tumors was not significantly different than those PPARγ low tumors. By preserving spatial relationships during the GeoMx analysis, we also identify a novel association between lower immune cell expression in the tumors and higher expression of β-catenin in the stroma, and differential expression of other WNT pathway members associated with PPARγ activity.Patients with the luminal I subtype rarely respond to ICIs(14,15), suggesting the existence of one or more immune escape mechanisms. We previously reported that the PPARγ/RxRa pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC (6,16). In tumors with high PPARγ pathway activity, CD8+ T-cell infiltration appears to be impaired through chemokine suppression, though additional mechanisms may also impact Tcell infiltration. These findings suggest that pharmacological inhibition of PPARγ may induce sensitivity to immunotherapies. To further our understanding of tumor-immune escape mechanisms in MIBC, analysis of both the tumor and the surrounding microenvironment is necessary. Comprehensive interrogation of the interaction between these two compartments has proved challenging thus far because most of the foundational work in MIBC has relied on commonly available assays such as single-plex immunohistochemistry (IHC) assays or bulk RNA expression and mutation profiling. With limited availability of tumor tissues during clinical trials, highly multiplexed and quant...

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Section: Discussioncontrasting

confidence: 99%

Defining the microenvironment landscape of bladder cancer using highly multiplexed spatial genomic and proteomic analysis

Reeves

Zhang²,

Norgaard

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…The early division between Uro and GU subtypes often persisted over multiple recurrences, which is in line with the mutually exclusive nature of these subtypes in a recent study on UBC and concomitant histologic variants. 47 The two entities Uro and GU, identified by unsupervised clustering of RNA profiles, mirror the marker profiles of hyperplasia and carcinoma in situ, respectively. 48 The molecular subtypes, therefore, provide a phenotypic correlate to the well-established "two pathway model" of bladder tumorigenesis that is rooted in histology and genetics.…”

Section: Discussionmentioning

confidence: 99%

Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma

Sjödahl

Eriksson

Patschan

et al. 2019

Intl Journal of Cancer

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Molecular changes occurring during invasion and clinical progression of cancer are difficult to study longitudinally in patient‐derived material. A unique feature of urothelial bladder cancer (UBC) is that patients frequently develop multiple nonmuscle invasive tumors, some of which may eventually progress to invade the muscle of the bladder wall. Here, we use a cohort of 73 patients that experienced a total of 357 UBC diagnoses to study the stability or change in detected molecular alterations during cancer progression. The tumors were subtyped by gene expression profiling and analyzed for hotspot mutations in FGFR3, PIK3CA and TERT, the most frequent early driver mutations in this tumor type. TP53 alterations, frequent in advanced UBC, were inferred from p53 staining pattern, and potential genomic alterations were inferred by gene expression patterns at regions harboring frequent copy number alterations. We show that early driver mutations were largely preserved in UBC recurrences. Changes in FGFR3, PIK3CA or TERT mutation status were not linked to changes in molecular subtype and aggressive behavior. Instead, changes into a more aggressive molecular subtype seem to be associated with p53 alterations. We analyze changes in gene expression from primary tumors, to recurrences and progression tumors, and identify two modes of progression: Patients for whom progression is preceded by or coincides with a radical subtype shift, and patients who progress without any systematic molecular changes. For the latter group of patients, progression may be either stochastic or depending on factors already present at primary tumor initiation.

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“…Some bladder tumours show histological and molecular intra-tumour heterogeneity 33,34 . Our consensus subtyping system addresses inter-tumour heterogeneity and focuses on defining the main molecular subtypes in MIBC.…”

Section: Discussionmentioning

confidence: 99%

The consensus molecular classification of muscle-invasive bladder cancer

Kamoun

Reyniès

Allory

et al. 2018

Preprint

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Muscle-Invasive Bladder Cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, yielding diverse sets of subtypes, which hampers the clinical implications of such knowledge.Here, we report the results of a large international effort to reach a consensus on MIBC molecular subtypes. Using 1750 MIBC transcriptomes and a network-based analysis of six independent MIBC classification systems, we identified a consensus set of six molecular classes: Luminal Papillary (24%), Luminal Non-Specified (8%), Luminal Unstable (15%), Stroma-rich (15%), Basal/Squamous (35%), and Neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics. This consensus system offers a robust framework that will enable testing and validating predictive biomarkers in future clinical trials.Bladder cancer is one of the most frequently diagnosed cancers in North America and Europe (4 th in men and 9 th in women). Most bladder cancers are urothelial carcinoma, which are classified for operational reasons as either non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). MIBC is usually diagnosed de novo, but may arise from the 10 to 20% of NMIBC cases that eventually progress. MIBC is the most aggressive disease state and is associated with a five-year survival rate of 60% for patients with localized disease, and less than 10% for patients with distant metastases.At the molecular level, MIBC is a heterogeneous disease that is characterized by genomic instability and a high mutation rate. Many chromosomal rearrangements and more than 50 oncogenes and tumour suppressor genes have been identified as recurrently altered 1,2 . Transcriptomic profiling facilitates stratifying bladder cancer into molecular subtypes in order to more precisely classify a patient's cancer according to prognosis and therapeutic options. Various teams have been working on the molecular stratification of bladder cancers, and several expression-based classification schemes have been proposed, either considering the full spectrum of bladder cancers 3-6 or focusing separately on MIBC 2,7-13 or on NMIBC 14 . These classifications have considerably advanced our understanding of bladder cancer biology; for example, the association between molecular subtypes and urothelial differentiation, and similarities between subtypes in bladder cancer and other cancers. In addition, specific genomic alterations were found to be enriched in particular molecular subtypes, including mutations targeting genes involved in cell cycle regulation, chromatin remodelling and receptor tyrosine kinase signaling. Importantly, several reports have highlighted the clinical importance of MIBC molecular stratification, suggesting that responses to chemotherapy and immunotherapy may be enriched in specific MIBC subtypes 9,15-17 .

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Intratumoral Heterogeneity of Bladder Cancer by Molecular Subtypes and Histologic Variants

Cited by 181 publications

References 10 publications

Defining the microenvironment landscape of bladder cancer using highly multiplexed spatial genomic and proteomic analysis

Defining the microenvironment landscape of bladder cancer using highly multiplexed spatial genomic and proteomic analysis

Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma

The consensus molecular classification of muscle-invasive bladder cancer

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