Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis
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...
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| Language: | English |
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BMC
2019-10-01
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| Series: | Genome Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s13073-019-0669-z |
| _version_ | 1828786914975547392 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Joep J. de Jong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T00:21:15Z |
| format | Article |
| id | doaj.art-f48f6e80fa2e412ea8f4dae7124976e4 |
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| language | English |
| last_indexed | 2024-12-12T00:21:15Z |
| publishDate | 2019-10-01 |
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| series | Genome Medicine |
| spelling | doaj.art-f48f6e80fa2e412ea8f4dae7124976e42022-12-22T00:44:44ZengBMCGenome Medicine1756-994X2019-10-0111111310.1186/s13073-019-0669-zLong non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosisJoep J. de Jong0Yang Liu1A. Gordon Robertson2Roland Seiler3Clarice S. Groeneveld4Michiel S. van der Heijden5Jonathan L. Wright6James Douglas7Marc Dall’Era8Simon J. Crabb9Bas W. G. van Rhijn10Kim E. M. van Kessel11Elai Davicioni12Mauro A. A. Castro13Yair Lotan14Ellen C. Zwarthoff15Peter C. Black16Joost L. Boormans17Ewan A. Gibb18Department of Urology, Erasmus MC Cancer InstituteDecipher Biosciences, IncCanada’s Michael Smith Genome Sciences Center, BC Cancer AgencyDepartment of Urology, University of BernBioinformatics and Systems Biology Laboratory, Federal University of Paraná, Polytechnic CenterDepartment of Medical Oncology, Netherlands Cancer InstituteDepartment of Urology, University of Washington School of MedicineDepartment of Urology, University Hospital of SouthamptonUC Davis Comprehensive Cancer CenterDepartment of Medical Oncology, University Hospital of SouthamptonDepartment of Surgical Oncology (Urology), Netherlands Cancer Institute – Antoni van Leeuwenhoek HospitalDepartment of Urology, Erasmus MC Cancer InstituteDecipher Biosciences, IncBioinformatics and Systems Biology Laboratory, Federal University of Paraná, Polytechnic CenterDepartment of Urology, UT Southwestern Medical CenterDepartment of Pathology, Erasmus MC University Medical Center RotterdamDepartment of Urologic Sciences, University of British ColumbiaDepartment of Urology, Erasmus MC Cancer InstituteDecipher Biosciences, IncAbstract 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.http://link.springer.com/article/10.1186/s13073-019-0669-zGene expression analysisLong non-coding RNAMolecular subtypesMuscle-invasive bladder cancer |
| spellingShingle | 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 Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis Genome Medicine Gene expression analysis Long non-coding RNA Molecular subtypes Muscle-invasive bladder cancer |
| title | Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis |
| title_full | Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis |
| title_fullStr | Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis |
| title_full_unstemmed | Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis |
| title_short | Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis |
| title_sort | long non coding rnas identify a subset of luminal muscle invasive bladder cancer patients with favorable prognosis |
| topic | Gene expression analysis Long non-coding RNA Molecular subtypes Muscle-invasive bladder cancer |
| url | http://link.springer.com/article/10.1186/s13073-019-0669-z |
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