An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer

SV Lindskrog, FF Prip, P Lamy, A Taber, CS Groeneveld, K Birkenkamp-Demtröder, J Jensen, T Strandgaard, I Nordentoft, E Christensen, M Sokac, NJ Birkbak, L Maretty, GG Hermann, AC Petersen, V Weyerer, MO Grimm, M Horstmann, G Sjödahl, M HöglundT Steiniche, K Mogensen, A de Reyniès, R Nawroth, B Jordan, X Lin, D Dragicevic, Douglas Ward, Anshita Goel, Carolyn D Hurst, JD Raman, JI Warrick, U Segersten, D Sikic, KEM van Kessel, T Maurer, JJ Meeks, DJ DeGraff, Rik Bryan, Margaret A Knowles, T Simic, A Hartmann, EC Zwarthoff, PU Malmström, N Malats, FX Real, Lars Dyrskjøt

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The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
Original languageEnglish
Article number2301
Number of pages18
JournalNature Communications
Publication statusPublished - 16 Apr 2021

Bibliographical note

Funding Information:
L.D. has sponsored research agreements with C2i-genomics, Natera, AstraZeneca and Ferring, and has an advisory/consulting role at Ferring. J.B.J. has sponsored research agreements with Medac, Photocure ASA, Cephaid, Nucleix, Astellas and Ferring, and has an advisory board role at Olympus Europe, Cephaid and Ferring. J.D.R. is involved in a sponsored scientific study or trial with Pacific Edge Biotechnologies, MDxHealth and Urogen Pharma, is a consultant for Urogen Pharma, and has an investment interest in American Kidney Stone Management. J.J.M. is a consultant for Ferring, AstraZeneca, Janssen and participated in advisory boards for Foundation Medicine and Nucleix. R.T.B. has contributed to advisory boards for Olympus Medical Systems & Janssen, and undertakes research funded by UroGen Pharma and QED Therapeutics. The following authors declare no competing interests: S.V.L., F.P., P.L., A.T., C.S.G., K.B.D., T.S., I.N., E.C., M.S., N.J.B., L.M., G.G.H., A.C.P., V.W., M.O.G., M.H., G.S., M.H., T.S., K.M., A.R., R.M., B.J., X.L., D.D., D.G.W., A.G., C.D.H., J.I.W., U.S., D.S., K.E.M.K., T.M., D.J.D., M.A.K., T.S., A.H., E.C.Z., P.U.M., N.M., and F.X.R.

Funding Information:
We thank K.K. Cheng, Maurice P. Zeegers, Nicholas D. James, Naheema S. Gordon, Ben Abbotts and Roland Arnold for work involved in generating the Birmingham RNA-Seq validation cohort. S.V.L., F.P., and L.D. are supported by the following funding sources: Aarhus University, The Danish Cancer Biobank, The Health Research Foundation of Central Denmark Region, The Danish Cancer Society. N.M. and F.X.R. are supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain (#PI18/ 01347), Asociación Española Contra el Cáncer (AECC, # GB28012014). D.J.D. is supported by the following funding sources: RSG 17-233–01-TBE from the American Cancer Society, the W.W. Smith Charitable Trust, the Pennsylvania Department of Health via Tobacco CURE Funds, the Ken and Bonnie Shockey Fund for Urologic Research and the Bladder Cancer Support Group at Penn State Health. J.I.W. is supported by the Laurence M. Demers Career Development Professorship in Pathology and Medicine, Pennsylvania State University. J.D.R. is supported by the Ken and Bonnie Shockey Fund for Urologic Research at Penn State Health. J.M. is funded by a SEED Award from the HOPE Foundation, the Department of Defense (W81XWH-18-0257), and the VHA (BX003692-01).

Publisher Copyright:
© 2021, The Author(s).


  • Aged
  • BCG Vaccine/administration & dosage
  • Biomarkers, Tumor/genetics
  • Carcinoma, Transitional Cell/genetics
  • Chromosomal Instability
  • Cystectomy/methods
  • Denmark/epidemiology
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Genomics
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mutation
  • Neoplasm Recurrence, Local/epidemiology
  • Prognosis
  • Progression-Free Survival
  • RNA-Seq
  • Urinary Bladder Neoplasms/genetics
  • Urinary Bladder/immunology

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology


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