Genome Medicine (Oct 2019)

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

DOI
https://doi.org/10.1186/s13073-019-0669-z
Journal volume & issue
Vol. 11, no. 1
pp. 1 – 13

Abstract

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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.

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