Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis

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

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Background: 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. Methods: 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). Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article number60
JournalGenome Medicine
Volume11
Issue number1
DOIs
StatePublished - Oct 17 2019

Keywords

  • Gene expression analysis
  • Long non-coding RNA
  • Molecular subtypes
  • Muscle-invasive bladder cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    De Jong, J. J., Liu, Y., Robertson, A. G., Seiler, R., Groeneveld, C. S., Van Der Heijden, M. S., Wright, J. L., Douglas, J., Dall'Era, M., Crabb, S. J., Van Rhijn, B. W. G., Van Kessel, K. E. M., Davicioni, E., Castro, M. A. A., Lotan, Y., Zwarthoff, E. C., Black, P. C., Boormans, J. L., & Gibb, E. A. (2019). Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis. Genome Medicine, 11(1), [60]. https://doi.org/10.1186/s13073-019-0669-z