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

Qianxing Mo, Fotis Nikolos, Fengju Chen, Zoe Tramel, Yu Cheng Lee, Kazukuni Hayashi, Jing Xiao, Jianjun Shen, Keith Syson Chan

    Research output: Contribution to journalArticlepeer-review

    105 Scopus citations


    Background: Muscle-invasive bladder cancers (MIBCs) cause approximately 150 000 deaths per year worldwide. Survival for MIBC patients is heterogeneous, with no clinically validated molecular markers that predict clinical outcome. Non-MIBCs (NMIBCs) generally have favorable outcome; however, a portion progress to MIBC. Hence, development of a prognostic tool that can guide decision-making is crucial for improving clinical management of bladder urothelial carcinomas. Methods: Tumor grade is defined by pathologic evaluation of tumor cell differentiation, and it often associates with clinical outcome. The current study extrapolates this conventional wisdom and combines it with molecular profiling. We developed an 18-gene signature that molecularly defines urothelial cellular differentiation, thus classifying MIBCs and NMIBCs into two subgroups: basal and differentiated. We evaluated the prognostic capability of this “tumor differentiation signature” and three other existing gene signatures including the The Cancer Genome Atlas (TCGA; 2707 genes), MD Anderson Cancer Center (MDA; 2252 genes/2697 probes), and University of North Carolina at Chapel Hill (UNC; 47 genes) using five gene expression data sets derived from MIBC and NMIBC patients. All statistical tests were two-sided. Results: The tumor differentiation signature demonstrated consistency and statistical robustness toward stratifying MIBC patients into different overall survival outcomes (TCGA cohort 1, P ¼ .03; MDA discovery, P ¼ .009; MDA validation, P ¼ .01), while the other signatures were not as consistent. In addition, we analyzed the progression (Ta/T1 progressing to >T2) probability of NMIBCs. NMIBC patients with a basal tumor differentiation signature associated with worse progression outcome (P ¼ .008). Gene functional term enrichment and gene set enrichment analyses revealed that genes involved in the biologic process of immune response and inflammatory response are among the most elevated within basal bladder cancers, implicating them as candidates for immune checkpoint therapies. Conclusions: These results provide definitive evidence that a biology-prioritizing clustering methodology generates meaningful insights into patient stratification and reveals targetable molecular pathways to impact future therapeutic approach.

    Original languageEnglish (US)
    Pages (from-to)448-459
    Number of pages12
    JournalJournal of the National Cancer Institute
    Issue number5
    StatePublished - May 1 2018

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research


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