Prognostic Power of a Tumor Differentiation Gene Signature for Bladder Urothelial Carcinomas

Mo, Qianxing; Nikolos, Fotis; Chen, Ken; Tramel, Zoe; Lee, Yu-Cheng; Hayashi, Kazukuni; Xiao, Jing; Shen, Jianjun; Chan, Keith S.

doi:10.1093/jnci/djx243

Cited by 136 publications

(124 citation statements)

References 45 publications

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“…Considering also the size of this subtype (17/98), these findings are in line with earlier observations, supporting that approximately 20% of NMIBC resemble MIBC at the molecular level . Moreover, NPS1 expressed features of antigen presentation, inflammation and was also enriched in IFN‐γ response pathway, in concordance with RNA‐based observations that high grade, aggressive basal subtypes both in MIBC and in NMIBC are presenting with an immune‐infiltrated phenotype . Proteins involved in DNA Damage Response and the Unfolded Protein Response were also consistently overexpressed in NPS1.…”

Section: Discussionsupporting

confidence: 88%

“…6 Moreover, NPS1 expressed features of antigen presentation, inflammation and was also enriched in IFN-γ response pathway, in concordance with RNA-based observations that high grade, aggressive basal subtypes both in MIBC and in NMIBC are presenting with an immune-infiltrated phenotype. 41,42 Proteins involved in DNA Damage Response and the Unfolded Protein Response were also consistently overexpressed in NPS1. Based on these observations, NPS1 tumors may likely respond to immune checkpoint, PARP or HSP inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

Stroggilos

Mokou

Latosinska

et al. 2019

Intl Journal of Cancer

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DNA/RNA‐based classification of bladder cancer (BC) supports the existence of multiple molecular subtypes, while investigations at the protein level are scarce. Here, we aimed to investigate if Nonmuscle Invasive Bladder Cancer (NMIBC) can be stratified to biologically meaningful groups based on the proteome. Tissue specimens from 117 patients at primary diagnosis (98 with NMIBC and 19 with MIBC), were processed for high‐resolution proteomics analysis by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). The proteomics output was subjected to unsupervised consensus clustering, principal component analysis (PCA) and investigation of subtype‐specific features, pathways, and gene sets. NMIBC patients were optimally stratified to three NMIBC proteomic subtypes (NPS), differing in size, clinicopathologic and molecular backgrounds: NPS1 (mostly high stage/grade/risk samples) was the smallest in size (17/98) and overexpressed proteins reflective of an immune/inflammatory phenotype, involved in cell proliferation, unfolded protein response and DNA damage response, whereas NPS2 (mixed stage/grade/risk composition) presented with an infiltrated/mesenchymal profile. NPS3 was rich in luminal/differentiation markers, in line with its pathological composition (mostly low stage/grade/risk samples). PCA revealed a close proximity of NPS1 and conversely, remoteness of NPS3 to the proteome of MIBC. Proteins distinguishing these two extreme subtypes were also found to consistently differ at the mRNA levels between high and low‐risk subtypes of the UROMOL and LUND cohorts. Collectively, our study identifies three proteomic NMIBC subtypes and following a cross‐omics validation in two independent cohorts, shortlists molecular features meriting further investigation for their biomarker or potentially therapeutic value.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

Stroggilos

Mokou

Latosinska

et al. 2019

Intl Journal of Cancer

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“…We used six published MIBC molecular classifications to define a unified consensus subtyping system. We refer to these input classifications as Baylor (Tumour differentiation) 13 , UNC 7 , CIT-Curie 8 , MDA 9 , Lund 10 , and TCGA 2 . Following the approach outlined in Extended data figure 1, we selected 18 MIBC mRNA datasets (n=1750, Supplementary Table 1), and assigned each sample to a subtype in each of the six classification systems.…”

Section: Published Molecular Classifications Of Mibc Converge On Six mentioning

confidence: 99%

“…The six classification systems were mainly built on transcriptomic data, as follows: Mo et al 13 We used these classifiers on 18 MIBC mRNA datasets (N = 1750 samples) profiled on ten different gene expression platforms ( Supplementary Table 1), and assigned each sample to a subtype in each of the six classification systems. 16…”

Section: Subtyping Of Mibc Samples According To Published Mibc Molecumentioning

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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“…A number of teams have reported molecular classifications of bladder cancers. Several expression-based schemes have been proposed, either considering the full spectrum of nonmetastatic bladder cancers [1][2][3][4][5][6], or focusing separately either on NMIBC [7,8] or on MIBC [9][10][11][12][13][14][15][16]. These classifications have considerably advanced our understanding of bladder cancer biology.…”

Section: Introductionmentioning

confidence: 99%