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- Title
Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis.
- Authors
de Jong, Joep J.; Liu, Yang; Robertson, A. Gordon; Seiler, Roland; Groeneveld, Clarice S.; van der Heijden, Michiel S.; Wright, Jonathan L.; Douglas, James; Dall'Era, Marc; Crabb, Simon J.; van Rhijn, Bas W. G.; van Kessel, Kim E. M.; Davicioni, Elai; Castro, Mauro A. A.; Lotan, Yair; Zwarthoff, Ellen C.; Black, Peter C.; Boormans, Joost L.; Gibb, Ewan A.
- 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.
- Subjects
NON-coding RNA; CANCER prognosis; BLADDER cancer; BREAST cancer prognosis; GENE expression profiling; CANCER patients; MESSENGER RNA
- Publication
Genome Medicine, 2019, Vol 11, Issue 1, pN.PAG
- ISSN
1756-994X
- Publication type
Article
- DOI
10.1186/s13073-019-0669-z