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Genetics and Genomics

Non-muscle-invasive micropapillary bladder cancer has a distinct lncRNA profile associated with unfavorable prognosis

British Journal of Cancer volume 127, pages 313–320 (2022)Cite this article

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Abstract

Background

Molecular subtyping of bladder cancer has revealed luminal tumors generally have a more favourable prognosis. However, some aggressive forms of variant histology, including micropapillary, are often classified luminal. In previous work, we found long non-coding RNA (lncRNA) expression profiles could identify a subgroup of luminal bladder tumors with less aggressive biology and better outcomes.

Objective

In the present study, we aimed to investigate whether lncRNA expression profiles could identify high-grade T1 micropapillary bladder cancer with differential outcome.

Design, setting, and participants

LncRNAs were quantified from RNA-seq data from a HGT1 bladder cancer cohort that was enriched for primary micropapillary cases (15/84). Unsupervised consensus clustering of variant lncRNAs identified a three-cluster solution, which was further characterised using a panel of micropapillary-associated biomarkers, molecular subtypes, gene signatures, and survival analysis. A single-sample genomic signature was trained using lasso-penalized logistic regression to classify micropapillary-like gene-expression, as characterised by lncRNA clustering. The genomic classifier (GC) was tested on luminal tumors derived from the TCGA cohort (N = 202).

Outcome measurements and statistical analysis

Patient and tumor characteristics were compared between subgroups by using X2 tests and two-sided Wilcoxon rank-sum tests. Primary endpoints were overall, progression-free and high-grade recurrence-free survival, calculated as the date of high-grade T1 disease at TURBT till date of death from any cause, progression, or recurrence, respectively. Survival rates were estimated using weighted Kaplan–Meier (KM) curves.

Results and limitations

Primary micropapillary HGT1 showed decreased FGFR3, SHH, and p53 pathway activity relative to tumors with conventional urothelial carcinoma. Many bladder cancer-associated lncRNAs were downregulated in micropapillary tumors, including UCA1, LINC00152, and MALAT1. Unsupervised consensus clustering resulted in a lncRNA cluster 1 (LC1) with worse prognosis that was enriched for primary micropapillary histology and the Luminal Unstable (LumU) molecular subtype. Interestingly, LC1 appeared to better identify aggressive HGT1 disease, compared to stratifying outcomes using primary histologic characteristics. A signature trained to identify LC1 cases showed good performance in the testing cohort, identifying seven cases with significantly worse survival (p < 0.001). Limitations include the retrospective nature of the study and the lack of a validation cohort.

Conclusions

Using the lncRNA transcriptome we identified a subgroup of aggressive HGT1 bladder cancer that was enriched with micropapillary histology. These data suggest that lncRNAs can facilitate the identification of aggressive micropapillary-like tumors, potentially improving patient management.

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Fig. 1: Differential gene expression differences between tumors with micropapillary histology and conventional urothelial carcinoma.
Fig. 2: Biological pathways differentially regulated between FGFR3 active (FGFR3+) urothelial (N = 7), micropapillary (N = 15) and remaining urothelial tumors (N = 62).
Fig. 3: Survival analysis stratified by micropapillary histology and by MP-LncCC.
Fig. 4: Biological characterisation of the MP-lncRNA cluster (MP-LncCC) using selected micropapillary marker genes.
Fig. 5: Biological and clinical characterisation of the FGFR3+ and MP+ cases in the subset of N = 202 luminal tumors from the TCGA cohort.

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Data availability

Gene expression data of the T1 cohort have been uploaded to GEO (GEO: GSE136401). The TCGA RNA-seq data was available as part of the TCGA research network (http://cancergenome.nih.gov/).

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Author information

Author notes

  1. These authors contributed equally: Ewan A. Gibb, Joaquim Bellmunt.

Authors and Affiliations

  1. Department of Urology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Joep J. de Jong

  2. Hospital Universitario Virgen del Rocio Sevilla, Sevilla, Spain

    Begoña P. Valderrama

  3. IMIM-Hospital del Mar and GRIB, Barcelona, Spain

    Julia Perera

  4. Department of Pathology, Parc de Salut Mar, Universitat Pompeu Fabra, Barcelona, Spain

    Nuria Juanpere

  5. Center for functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA, USA

    Paloma Cejas & Henry Long

  6. Evolutionary Genomics Group, Research Programme on Biomedical Informatics, Hospital del Mar Medical Research Institute (IMIM) and Universitat Pompeu Fabra (UPF), Barcelona, Spain

    M. Mar Albà

  7. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain

    M. Mar Albà

  8. Veracyte Inc., Vancouver, BC, Canada

    Ewan A. Gibb

  9. Beth Israel Deaconess Medical Center, PSMAR-IMIM Lab, Harvard Medical School, Boston, MA, USA

    Joaquim Bellmunt

Authors
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Contributions

JJdJ, EAG, and JB designed the study. JJdJ performed gene expression analyses and classifier development, with suggestions from EAG and JB. JJdJ, EAG, and JB wrote the manuscript with feedback from all authors. JJdJ, EAG., JB, JP, and MA curated data for the study. All authors provided critical review and revisions, and all authors approved the final version of the manuscript for submission and publication. EAG and JB contributed equally. EAG and JB contributed equally, had full access to all the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding authors

Correspondence to Ewan A. Gibb or Joaquim Bellmunt.

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Competing interests

Ewan Gibb is an employee of Veracyte, Inc. The remaining authors declare no competing interests.

Ethics approval and consent to participate

Informed consent was provided by each subject and the use of the tissue was approved by the Ethics Committee of the Dana Farber Cancer Institute, Hospital del Mar and Hospital Vall d’Hebron and all research complied with local ethics guidelines.

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de Jong, J.J., Valderrama, B.P., Perera, J. et al. Non-muscle-invasive micropapillary bladder cancer has a distinct lncRNA profile associated with unfavorable prognosis. Br J Cancer 127, 313–320 (2022). https://doi.org/10.1038/s41416-022-01799-2

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