Comprehensive Gene Expression Analysis in NMIBC Using RNA-seq Reveals New Therapy Strategies

Chen, Xiaoliang; Jiang, Fuquan; Chen, Jia; Liu, Ming; Nan, Yong-Hao; Qu, Licheng; Kong, Qingkuo; Hou, Fangfang; Luo, Wenshan; Na, Wanli; Jin, Xin; Tan, Jiufeng

doi:10.3389/fonc.2019.00523

Cited by 11 publications

(7 citation statements)

References 33 publications

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“…In NMIBC cohorts, Patschan et al demonstrated increased CD3 + infiltration in GU and basal/ SCCL tumors compared with URO tumors [13]. Additional research in NMIBC has demonstrated that CD3D, an immune response gene involved in T-cell signaling, is associated with poor prognosis when expressed at low levels [45]. Therefore, a lack of immune infiltration and adequate immune signaling in the URO subtype may explain the resulting poor RFS post-BCG treatment.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and prognostic implications of a three‐antibody molecular subtyping algorithm for non‐muscle invasive bladder cancer

Jackson

Chen

Hardy

et al. 2021

The Journal of Pathology CR

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Intrinsic molecular subtypes may explain marked variation between bladder cancer patients in prognosis and response to therapy. Complex testing algorithms and little attention to more prevalent, early-stage (non-muscle invasive) bladder cancers (NMIBCs) have hindered implementation of subtyping in clinical practice. Here, using a three-antibody immunohistochemistry (IHC) algorithm, we identify the diagnostic and prognostic associations of well-validated proteomic features of basal and luminal subtypes in NMIBC. By IHC, we divided 481 NMIBCs into basal (GATA3 À /KRT5 + ) and luminal (GATA3 + /KRT5 variable) subtypes. We further divided the luminal subtype into URO (p16 low), URO-KRT5 + (KRT5 + ), and genomically unstable (GU) (p16 high) subtypes. Expression thresholds were confirmed using unsupervised hierarchical clustering. Subtypes were correlated with pathology and outcomes. All NMIBC cases clustered into the basal/squamous (basal) or one of the three luminal (URO, URO-KRT5 + , and GU) subtypes. Although uncommon in this NMIBC cohort, basal tumors (3%, n = 16) had dramatically higher grade (100%, n = 16, odds ratio [OR] = 13, relative risk = 3.25) and stage, and rapid progression to muscle invasion (median progression-free survival = 35.4 months, p = 0.0001). URO, the most common subtype (46%, n = 220), showed rapid recurrence (median recurrence-free survival [RFS] = 11.5 months, p = 0.039) compared to its GU counterpart (29%, n = 137, median RFS = 16.9 months), even in patients who received intravesical immunotherapy (p = 0.049). URO-KRT5 + tumors (22%, n = 108) were typically low grade (66%, n = 71, OR = 3.7) and recurred slowly (median RFS = 38.7 months). Therefore, a simple immunohistochemical algorithm can identify clinically relevant molecular subtypes of NMIBC. In routine clinical practice, this three-antibody algorithm may help clarify diagnostic dilemmas and optimize surveillance and treatment strategies for patients.

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Section: Discussionmentioning

confidence: 99%

Diagnostic and prognostic implications of a three‐antibody molecular subtyping algorithm for non‐muscle invasive bladder cancer

Jackson

Chen

Hardy

et al. 2021

The Journal of Pathology CR

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“…The development of gene classifiers and subtyping using microarrays is another option for combining molecular information [25,26]. In a large prospective Scandinavian-based trial of 1224 patients, Dyrskjøt et al demonstrated that the results of a 12-gene real-time qualitative PCR assay yielded independent prognostic information on tumor progression [27].…”

Section: Prognostic Markers For Disease Progressionmentioning

confidence: 99%

Bladder Cancer Tissue-Based Biomarkers

Soria¹,

Sänchez‐Carbayo

Benderska-Söder³

et al. 2021

Société Internationale D’Urologie Journal

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This review aims to provide a practical update regarding the current role of tissue-based biomarkers in bladder cancer. Their prognostic and predictive role both in non-muscle-invasive (NMIBC) and in muscle-invasive disease (MIBC) has been reviewed with particular focus to their use in clinical practice. In summary, the literature on the prediction of disease recurrence in NMIBC is inconclusive, and there is little information on prediction of response to intravesical bacillus Calmette-Guerin (BCG). Concerning disease progression, external prospective validation studies suggest that FGFR3 mutation status and gene signatures may improve models that are based only on clinicopathologic information. In MIBC, tissue-based biomarkers are increasingly important, since they may predict the response to systemic chemotherapy and immunotherapy. In particular, the advent of molecular characterization promises to revolutionize the paradigm of decision-making in the treatment of MIBC. Molecular subtyping has been shown to improve the prediction of pathological stage at RC and to predict the response to systemic chemotherapy and immunotherapy. However, external and prospective validations are warranted to confirm these preliminary findings. Several different tissue-based biomarkers such as PD-1/PD-L1 expression, tumor mutational burden, and the analysis of tumor microenvironment, may in future play a role in selecting patients for systemic immunotherapy. However, to date, no pretreatment recommendations can be definitively made on the basis of any molecular predictors. In conclusion, despite the potential of tissue-based biomarkers, their use in bladder cancer should be limited to experimental settings.

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“…To overcome these limitations, investigations have been conducted to find biomarkers based on cancer tissue gene expression profiles. Certain mRNA markers accurately predict cancer prognosis [ 18 , 19 ]. Transcriptome profiling using cancer tissue samples could lead to the discovery of precise molecular markers for cancer diagnosis and prognosis [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Integrative Transcriptome Profiling Reveals SKA3 as a Novel Prognostic Marker in Non-Muscle Invasive Bladder Cancer

You

Piao

Kang

et al. 2021

Cancers

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Approximately 80% of all new bladder cancer patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). However, approximately 15% of them progress to muscle-invasive bladder cancer (MIBC), for which prognosis is poor. The current study aimed to improve diagnostic accuracy associated with clinical outcomes in NMIBC patients. Nevertheless, it has been challenging to identify molecular biomarkers that accurately predict MIBC progression because this disease is complex and heterogeneous. Through integrative transcriptome profiling, we showed that high SKA3 expression is associated with poor clinical outcomes and MIBC progression. We performed RNA sequencing on human tumor tissues to identify candidate biomarkers in NMIBC. We then selected genes with prognostic significance by analyzing public datasets from multiple cohorts of bladder cancer patients. We found that SKA3 was associated with NMIBC pathophysiology and poor survival. We analyzed public single-cell RNA-sequencing (scRNA-seq) data for bladder cancer to dissect transcriptional tumor heterogeneity. SKA3 was expressed in an epithelial cell subpopulation expressing genes regulating the cell cycle. Knockdown experiments confirmed that SKA3 promotes bladder cancer cell proliferation by accelerating G2/M transition. Hence, SKA3 is a new prognostic marker for predicting NMIBC progression. Its inhibition could form part of a novel treatment lowering the probability of bladder cancer progression.

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Comprehensive Gene Expression Analysis in NMIBC Using RNA-seq Reveals New Therapy Strategies

Cited by 11 publications

References 33 publications

Diagnostic and prognostic implications of a three‐antibody molecular subtyping algorithm for non‐muscle invasive bladder cancer

Diagnostic and prognostic implications of a three‐antibody molecular subtyping algorithm for non‐muscle invasive bladder cancer

Bladder Cancer Tissue-Based Biomarkers

Integrative Transcriptome Profiling Reveals SKA3 as a Novel Prognostic Marker in Non-Muscle Invasive Bladder Cancer

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