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Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

ABSTRACT: The progression of conventional urothelial carcinoma (UC) of the bladder to a tumor with a mesenchymal phenotype, referred to as sarcomatoid carcinoma (SARC), is signified by a high propensity for regional and distant metastasis resulting in shorter survival. We report a comprehensive retrospective analysis of 28 cases of SARCs and 84 cases of conventional UCs. A TCGA cohort of 408 muscle-invasive bladder cancers was used as a reference cohort. SARCs showed a distinct mutational landscape with enrichment of p53, PIK3CA, and RB1 mutations. They developed from basal precursor conventional UCs and could be divided into a basal subtype and the most aggressive mesenchymal subtype. Expression analysis showed that SARCs are driven by dysregulation of cell cycle and EMT regulatory networks and nearly half exhibited an immune infiltration phenotype with PDL1 upregulation. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128192 | GEO | 2019/05/07

REPOSITORIES: GEO

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Project description:Background: Neoadjuvant chemotherapy (NAC) is the standard treatment for muscle-invasive bladder cancer (MIBC), yet 40% of patients progress, emphasizing the need for biomarkers predictive for response or chemoresistance. Gene expression-based subtypes may serve as biomarkers, though which subtypes will respond, notably when it comes to the basal subtype, remains contentious. Patients and methods: This post hoc study analyzed 300 NAC-treated patients enrolled in the GETUG/AFU VESPER trial, with transurethral diagnostic formalin-ﬁxed parafﬁn-embedded which underwent pathological review before being sequenced. ‘Mixed’ subtype was deﬁned for tumors displaying at least two different Consensus molecular subtypes in separate regions. We evaluated the association between molecular subtypes and outcome after NAC. Tumors with remaining tissue at cystectomy (n ¼ 83) were compared with pre-treatment tumors. Results: Cases were classiﬁed basal/squamous (Ba/Sq) (n ¼ 84), luminal unstable (n = 57), stroma-rich (n = 53), mixed (n = 48), luminal papillary (n ¼ 39), luminal non-speciﬁc (n = 18), and neuroendocrine-like (n ¼ 1), with 30/48 mixed cases including a Ba/Sq component. Compared with other molecular subtypes in a multivariate Cox model, Ba/Sq (pure or mixed) patients had an increased hazard ratio (HR) of progression-free survival [HR 2.0, 95% conﬁdence interval (CI) 1.36-3.0]. Mixed tumors were associated with decreased metabolic activity that could account for chemoresistance. Ba/Sq and mixed non-responders mostly maintained their subtype at cystectomy and have fewer myeloid dendritic cells after NAC. Tumors classiﬁed luminal papillary at transurethral resection of the urinary bladder tumor exhibited an increase in T CD4þ and macrophage signatures after NAC. Other subtypes did not show signiﬁcant immune changes after NAC. Our study design relied on detailed pathological review, which precluded evaluating the mixed subtype in published datasets. Furthermore, the sample size for post-NAC analyses constrained the statistical power of these ﬁndings. Conclusions: Our ﬁndings underscore the importance of recognizing intra-tumor heterogeneity in MIBC and its role in chemoresistance associated with Ba/Sq subtype, and provide valuable insights that could help future treatment development and improve patient outcomes.

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Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

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