Identification of Distinct Basal and Luminal Subtypes of Muscle-Invasive Bladder Cancer with Different Sensitivities to Frontline Chemotherapy

• Published in: Cancer cell Vol. 25; no. 2; pp. 152 - 165
• Main Authors: Choi, Woonyoung, Porten, Sima, Kim, Seungchan, Willis, Daniel, Plimack, Elizabeth R., Hoffman-Censits, Jean, Roth, Beat, Cheng, Tiewei, Tran, Mai, Lee, I-Ling, Melquist, Jonathan, Bondaruk, Jolanta, Majewski, Tadeusz, Zhang, Shizhen, Pretzsch, Shanna, Baggerly, Keith, Siefker-Radtke, Arlene, Czerniak, Bogdan, Dinney, Colin P.N., McConkey, David J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.02.2014
• Subjects: Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor - genetics; Blotting, Western; Carcinoma, Basal Cell - drug therapy; Carcinoma, Basal Cell - pathology; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Cell Differentiation; Cell Proliferation; Cisplatin - administration & dosage; Clinical Trials, Phase II as Topic; Cohort Studies; Doxorubicin - administration & dosage; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Profiling; Humans; Male; Methotrexate - administration & dosage; MicroRNAs - genetics; Muscle Neoplasms - classification; Muscle Neoplasms - drug therapy; Muscle Neoplasms - pathology; Mutation - genetics; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; PPAR gamma - genetics; PPAR gamma - metabolism; Prognosis; Real-Time Polymerase Chain Reaction; Receptor, Fibroblast Growth Factor, Type 3 - genetics; Receptor, Fibroblast Growth Factor, Type 3 - metabolism; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Tumor Suppressor Protein p53 - genetics; Urinary Bladder Neoplasms - classification; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - pathology; Vinblastine - administration & dosage
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccr.2014.01.009

Muscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy. •Chemoresistant bladder cancers express active p53-like gene expression signatures•Bladder cancers form basal and luminal subtypes like those found in breast cancer•Squamous features are characteristic of basal bladder cancers•p63 and PPARγ play opposing roles in controlling basal and luminal biology Choi et al. define three molecular subtypes of muscle-invasive bladder cancer, a disease with heterogeneous clinical outcomes and responses to conventional chemotherapy. Luminal and basal subtypes resemble the equivalent molecular subtypes of breast cancer, whereas a p53-like subtype displays chemoresistance.