Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease, and gene expression profiling has identified several molecular subtypes with distinct biological and clinicopathological characteristics. While MIBC subtyping has primarily been based on messenger RNA (mRNA), long non-coding RNAs (lncRNAs) may provide additional resolution.
LncRNA expression was quantified from microarray data of a MIBC cohort treated with neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) (n = 223). Unsupervised consensus clustering of highly variant lncRNAs identified a four-cluster solution, which was characterized using a panel of MIBC biomarkers, regulon activity profiles, gene signatures, and survival analysis. The four-cluster solution was confirmed in The Cancer Genome Atlas (TCGA) cohort (n = 405). A single-sample genomic classifier (GC) was trained using ridge-penalized logistic regression and validated in two independent cohorts (n = 255 and n = 94).
NAC and TCGA cohorts both contained an lncRNA cluster (LC3) with favorable prognosis that was enriched with tumors of the luminal-papillary (LP) subtype. In both cohorts, patients with LP tumors in LC3 (LPL-C3) were younger and had organ-confined, node-negative disease. The LPL-C3 tumors had enhanced FGFR3, SHH, and wild-type p53 pathway activity. In the TCGA cohort, LPL-C3 tumors were enriched for FGFR3 mutations and depleted for TP53 and RB1 mutations. A GC trained to identify these LPL-C3 patients showed robust performance in two validation cohorts.
Using lncRNA expression profiles, we identified a biologically distinct subgroup of luminal-papillary MIBC with a favorable prognosis. These data suggest that lncRNAs provide additional information for higher-resolution subtyping, potentially improving precision patient management.
Genome medicine. 2019 Oct 17*** epublish ***
Joep J de Jong, Yang Liu, A Gordon Robertson, Roland Seiler, Clarice S Groeneveld, Michiel S van der Heijden, Jonathan L Wright, James Douglas, Marc Dall'Era, Simon J Crabb, Bas W G van Rhijn, Kim E M van Kessel, Elai Davicioni, Mauro A A Castro, Yair Lotan, Ellen C Zwarthoff, Peter C Black, Joost L Boormans, Ewan A Gibb
Department of Urology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. ., Decipher Biosciences, Inc, Vancouver, British Columbia, Canada., Canada's Michael Smith Genome Sciences Center, BC Cancer Agency, Vancouver, British Columbia, Canada., Department of Urology, University of Bern, Bern, Switzerland., Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, Polytechnic Center, Curitiba, Brazil., Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Department of Urology, University of Washington School of Medicine, Seattle, WA, USA., Department of Urology, University Hospital of Southampton, Hampshire, UK., UC Davis Comprehensive Cancer Center, Sacramento, CA, USA., Department of Medical Oncology, University Hospital of Southampton, Hampshire, UK., Department of Surgical Oncology (Urology), Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands., Department of Urology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA., Department of Pathology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands., Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.