Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

Abstract

Summary We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival ‘neuronal’ subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, lncRNA, and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma-in-situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.

A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers

“…Notably, the ASC signature performed better than other stem cell signatures tested (Figure 4D). A recent characterization of muscle invasive bladder cancers included a minor fraction of samples (~ 1%) histologically defined as small cell neuroendocrine or a mixed phenotype with a small cell neuroendocrine component (Robertson et al, 2017). Comparing the ASC signature scores between the SCN and non-SCN bladder cancers revealed that the SCN bladder cancers were significantly more adult stem cell-like (Figure 4E).…”

FOXM1 predicts disease progression in non-muscle invasive bladder cancer

“…Thus molecular biomarkers are needed to improve prediction of treatment response or even for clinical decision-making in the sense of preemptive biomarkers (Youssef and Lotan 2011; Kluth et al 2015). Based on recent data, the most promising results were provided by gene expression signatures of TURB samples and by liquid biopsies from urine or blood (Contreras-Sanz et al 2017; Robertson et al 2017). The elucidation of valuable invasive or non-invasive biomarkers or drug targets is still at its beginning.…”

“…We have recently shown that FOXM1 is a predictor for overall and disease-specific survival in muscle invasive bladder cancer (MIBC) superior to the TNM staging system and MKI67 (Rinaldetti et al 2017). A recent TCGA study further underlined the role of FOXM1 as regulator in MIBC (Robertson et al 2017). As MKI67 is considered as the gold standard biomarker for proliferation and prognosis, the impact of FOXM1 needs yet again to be compared with the later (Rodríguez-Alonso et al 2002).…”

“…Recent findings showed that bladder cancer can be subclassified in molecular subtypes with some similarities to breast cancer subtypes (Choi et al 2014; Hedegaard et al 2016; Robertson et al 2017). These findings open the doors for personalized treatment concepts similar to those in breast cancer.…”

Multi-omic profiling refines the molecular view

“…These data move the field considerably closer to a comprehensive catalogue of molecular features and have enabled the influence of molecular subtype on patient outcomes to be examined at a much greater level of detail. The rich dataset includes whole-exome, mRNA, long non-coding RNA (lncRNA), and microRNA sequencing data, DNA copy number variation and methylation data, and reverse-phase protein array data 1 . The tumours analysed were chemotherapy naive and the majority (86%) were pure urothelial carcinomas.…”