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Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis de Jong, Joep J.; Liu, Yang; Robertson, A. G.; Seiler, Roland; Groeneveld, Clarice S.; van der Heijden, Michiel S.; Wright, Jonathan L.; Douglas, James; Dall’Era, Marc; Crabb, Simon J.; et al.
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.
Item Metadata
Title |
Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis
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Creator |
de Jong, Joep J.; Liu, Yang; Robertson, A. G.; 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.
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Publisher |
BioMed Central
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Date Issued |
2019-10-17
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Description |
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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Subject | |
Genre | |
Type | |
Language |
eng
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Date Available |
2019-10-21
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution 4.0 International (CC BY 4.0)
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DOI |
10.14288/1.0384617
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URI | |
Affiliation | |
Citation |
Genome Medicine. 2019 Oct 17;11(1):60
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Publisher DOI |
10.1186/s13073-019-0669-z
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Peer Review Status |
Reviewed
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Scholarly Level |
Faculty
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Copyright Holder |
The Author(s).
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution 4.0 International (CC BY 4.0)