1. Identification of Distinct Basal and Luminal Subtypes of Muscle-Invasive Bladder Cancer with Different Sensitivities to Frontline Chemotherapy
- Author
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Daniel L. Willis, Jonathan Melquist, Beat Roth, Jean H. Hoffman-Censits, Woonyoung Choi, I-Ling Lee, Shanna Pretzsch, Keith A. Baggerly, Tiewei Cheng, Tadeusz Majewski, Sima P. Porten, Jolanta Bondaruk, Bogdan Czerniak, Shizhen Zhang, Colin P.N. Dinney, Elizabeth R. Plimack, Seungchan Kim, Mai Tran, Arlene O. Siefker-Radtke, and David J. McConkey
- Subjects
Male ,Cancer Research ,Fibroblast Growth Factor ,medicine.medical_treatment ,Basal Cell ,Messenger ,Drug Resistance ,Estrogen receptor ,Cohort Studies ,0302 clinical medicine ,Receptors ,Antineoplastic Combined Chemotherapy Protocols ,Neoadjuvant therapy ,Cancer ,Muscle Neoplasms ,0303 health sciences ,Tumor ,Blotting ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Differentiation ,Prognosis ,Neoadjuvant Therapy ,3. Good health ,Vinblastine ,Receptors, Estrogen ,Oncology ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Female ,Western ,Type 3 ,Receptor ,medicine.drug ,Urologic Diseases ,Blotting, Western ,Oncology and Carcinogenesis ,Biology ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Clinical Trials, Phase II as Topic ,Breast cancer ,Breast Cancer ,Biomarkers, Tumor ,Genetics ,medicine ,Receptor, Fibroblast Growth Factor, Type 3 ,Humans ,Neoplasm Invasiveness ,Clinical Trials ,Doxorubicin ,RNA, Messenger ,Oncology & Carcinogenesis ,Neoplasm Staging ,Cell Proliferation ,Aged ,030304 developmental biology ,Cisplatin ,Chemotherapy ,Bladder cancer ,Gene Expression Profiling ,Carcinoma ,Phase II as Topic ,Neurosciences ,Cell Biology ,medicine.disease ,Estrogen ,PPAR gamma ,MicroRNAs ,Methotrexate ,Squamous Cell ,Urinary Bladder Neoplasms ,Carcinoma, Basal Cell ,Drug Resistance, Neoplasm ,Mutation ,Cancer research ,RNA ,Neoplasm ,Tumor Suppressor Protein p53 ,Biomarkers - Abstract
SummaryMuscle-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.
- Published
- 2014
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