title: Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy.
abstract: 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.
authors: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Woonyoung
authors: W
authors: Choi
authors: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Sima
authors: S
authors: Porten
authors: Computational Biology Division, Translational Genomics Research Institute, 445N, Fifth Street, Phoenix, AZ 85004, USA.
authors: Seungchan
authors: S
authors: Kim
authors: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Daniel
authors: D
authors: Willis
authors: Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors: Elizabeth R
authors: ER
authors: Plimack
authors: Department of Medical Oncology, Thomas Jefferson University Hospital, 1025 Walnut Street, Suite 700, Philadelphia, PA 19107, USA.
authors: Jean
authors: J
authors: Hoffman-Censits
authors: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Beat
authors: B
authors: Roth
authors: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas-Graduate School of Biomedical Sciences (GSBS) at Houston, Houston, TX 77030, USA.
authors: Tiewei
authors: T
authors: Cheng
authors: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas-Graduate School of Biomedical Sciences (GSBS) at Houston, Houston, TX 77030, USA.
authors: Mai
authors: M
authors: Tran
authors: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: I-Ling
authors: IL
authors: Lee
authors: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Jonathan
authors: J
authors: Melquist
authors: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Jolanta
authors: J
authors: Bondaruk
authors: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Tadeusz
authors: T
authors: Majewski
authors: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Shizhen
authors: S
authors: Zhang
authors: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Shanna
authors: S
authors: Pretzsch
authors: Department of Bioinformatics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Keith
authors: K
authors: Baggerly
authors: Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Arlene
authors: A
authors: Siefker-Radtke
authors: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Bogdan
authors: B
authors: Czerniak
authors: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Colin P N
authors: CP
authors: Dinney
authors: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas-Graduate School of Biomedical Sciences (GSBS) at Houston, Houston, TX 77030, USA. Electronic address: dmcconke@mdanderson.org.
authors: David J
authors: DJ
authors: McConkey
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002945:Cisplatin / Q000008:administration & dosage; D017322:Clinical Trials, Phase II as Topic; D015331:Cohort Studies; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D035683:MicroRNAs / Q000235:genetics; D019042:Muscle Neoplasms / Q000145:classification / Q000188:drug therapy / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000145:classification / Q000188:drug therapy / Q000473:pathology*; D014747:Vinblastine / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D047495:PPAR gamma; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014747:Vinblastine; D004317:Doxorubicin; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D002945:Cisplatin; D008727:Methotrexate