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

Sia Viborg Lindskrog; Frederik Prip; Philippe Lamy; Ann Taber; Clarice S. Groeneveld; Karin Birkenkamp-Demtröder; Jørgen Bjerggaard Jensen; Trine Strandgaard; Iver Nordentoft; Emil Christensen; Mateo Sokac; Nicolai J. Birkbak; Lasse Maretty; Gregers G. Hermann; Astrid C. Petersen; Veronika Weyerer; Marc Oliver Grimm; Marcus Horstmann; Gottfrid Sjödahl; Mattias Höglund; Torben Steiniche; Karin Mogensen; Aurélien de Reyniès; Roman Nawroth; Brian Jordan; Xiaoqi Lin; Dejan Dragicevic; Douglas G. Ward; Anshita Goel; Carolyn D. Hurst; Jay D. Raman; Joshua I. Warrick; Ulrika Segersten; Danijel Sikic; Kim E.M. van Kessel; Tobias Maurer; Joshua J. Meeks; David J. DeGraff; Richard T. Bryan; Margaret A. Knowles; Tatjana Simic; Arndt Hartmann; Ellen C. Zwarthoff; Per Uno Malmström; Núria Malats; Francisco X. Real; Lars Dyrskjøt

doi:10.1038/s41467-021-22465-w

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

Sia Viborg Lindskrog, Frederik Prip, Philippe Lamy, Ann Taber, Clarice S. Groeneveld, Karin Birkenkamp-Demtröder, Jørgen Bjerggaard Jensen, Trine Strandgaard, Iver Nordentoft, Emil Christensen, Mateo Sokac, Nicolai J. Birkbak, Lasse Maretty, Gregers G. Hermann, Astrid C. Petersen, Veronika Weyerer, Marc Oliver Grimm, Marcus Horstmann, Gottfrid Sjödahl, Mattias HöglundTorben Steiniche, Karin Mogensen, Aurélien de Reyniès, Roman Nawroth, Brian Jordan, Xiaoqi Lin, Dejan Dragicevic, Douglas G. Ward, Anshita Goel, Carolyn D. Hurst, Jay D. Raman, Joshua I. Warrick, Ulrika Segersten, Danijel Sikic, Kim E.M. van Kessel, Tobias Maurer, Joshua J. Meeks, David J. DeGraff, Richard T. Bryan, Margaret A. Knowles, Tatjana Simic, Arndt Hartmann, Ellen C. Zwarthoff, Per Uno Malmström, Núria Malats, Francisco X. Real, Lars Dyrskjøt^*

^*Corresponding author for this work

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Abstract

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 language	English
Article number	2301
Journal	Nature Communications
Volume	12
Issue number	1
Number of pages	18
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-021-22465-w
Publication status	Published - 16 Apr 2021

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© 2021, The Author(s).

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Lindskrog et al (2021) An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancerFinal published version, 2.6 MBLicence: CC BY 4.0

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Lindskrog, S. V., Prip, F., Lamy, P., Taber, A., Groeneveld, C. S., Birkenkamp-Demtröder, K., Jensen, J. B., Strandgaard, T., Nordentoft, I., Christensen, E., Sokac, M., Birkbak, N. J., Maretty, L., Hermann, G. G., Petersen, A. C., Weyerer, V., Grimm, M. O., Horstmann, M., Sjödahl, G., ... Dyrskjøt, L. (2021). An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nature Communications, 12(1), Article 2301. https://doi.org/10.1038/s41467-021-22465-w

@article{29f4d3548f414117ae72c0c56428f55e,

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

abstract = "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.",

author = "Lindskrog, {Sia Viborg} and Frederik Prip and Philippe Lamy and Ann Taber and Groeneveld, {Clarice S.} and Karin Birkenkamp-Demtr{\"o}der and Jensen, {J{\o}rgen Bjerggaard} and Trine Strandgaard and Iver Nordentoft and Emil Christensen and Mateo Sokac and Birkbak, {Nicolai J.} and Lasse Maretty and Hermann, {Gregers G.} and Petersen, {Astrid C.} and Veronika Weyerer and Grimm, {Marc Oliver} and Marcus Horstmann and Gottfrid Sj{\"o}dahl and Mattias H{\"o}glund and Torben Steiniche and Karin Mogensen and {de Reyni{\`e}s}, Aur{\'e}lien and Roman Nawroth and Brian Jordan and Xiaoqi Lin and Dejan Dragicevic and Ward, {Douglas G.} and Anshita Goel and Hurst, {Carolyn D.} and Raman, {Jay D.} and Warrick, {Joshua I.} and Ulrika Segersten and Danijel Sikic and {van Kessel}, {Kim E.M.} and Tobias Maurer and Meeks, {Joshua J.} and DeGraff, {David J.} and Bryan, {Richard T.} and Knowles, {Margaret A.} and Tatjana Simic and Arndt Hartmann and Zwarthoff, {Ellen C.} and Malmstr{\"o}m, {Per Uno} and N{\'u}ria Malats and Real, {Francisco X.} and Lars Dyrskj{\o}t",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = apr,

day = "16",

doi = "10.1038/s41467-021-22465-w",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Lindskrog, SV, Prip, F, Lamy, P, Taber, A, Groeneveld, CS, Birkenkamp-Demtröder, K, Jensen, JB, Strandgaard, T, Nordentoft, I, Christensen, E, Sokac, M, Birkbak, NJ, Maretty, L, Hermann, GG, Petersen, AC, Weyerer, V, Grimm, MO, Horstmann, M, Sjödahl, G, Höglund, M, Steiniche, T, Mogensen, K, de Reyniès, A, Nawroth, R, Jordan, B, Lin, X, Dragicevic, D, Ward, DG, Goel, A, Hurst, CD, Raman, JD, Warrick, JI, Segersten, U, Sikic, D, van Kessel, KEM, Maurer, T, Meeks, JJ, DeGraff, DJ, Bryan, RT, Knowles, MA, Simic, T, Hartmann, A, Zwarthoff, EC, Malmström, PU, Malats, N, Real, FX & Dyrskjøt, L 2021, 'An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer', Nature Communications, vol. 12, no. 1, 2301. https://doi.org/10.1038/s41467-021-22465-w

TY - JOUR

T1 - An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer

AU - Lindskrog, Sia Viborg

AU - Prip, Frederik

AU - Lamy, Philippe

AU - Taber, Ann

AU - Groeneveld, Clarice S.

AU - Birkenkamp-Demtröder, Karin

AU - Jensen, Jørgen Bjerggaard

AU - Strandgaard, Trine

AU - Nordentoft, Iver

AU - Christensen, Emil

AU - Sokac, Mateo

AU - Birkbak, Nicolai J.

AU - Maretty, Lasse

AU - Hermann, Gregers G.

AU - Petersen, Astrid C.

AU - Weyerer, Veronika

AU - Grimm, Marc Oliver

AU - Horstmann, Marcus

AU - Sjödahl, Gottfrid

AU - Höglund, Mattias

AU - Steiniche, Torben

AU - Mogensen, Karin

AU - de Reyniès, Aurélien

AU - Nawroth, Roman

AU - Jordan, Brian

AU - Lin, Xiaoqi

AU - Dragicevic, Dejan

AU - Ward, Douglas G.

AU - Goel, Anshita

AU - Hurst, Carolyn D.

AU - Raman, Jay D.

AU - Warrick, Joshua I.

AU - Segersten, Ulrika

AU - Sikic, Danijel

AU - van Kessel, Kim E.M.

AU - Maurer, Tobias

AU - Meeks, Joshua J.

AU - DeGraff, David J.

AU - Bryan, Richard T.

AU - Knowles, Margaret A.

AU - Simic, Tatjana

AU - Hartmann, Arndt

AU - Zwarthoff, Ellen C.

AU - Malmström, Per Uno

AU - Malats, Núria

AU - Real, Francisco X.

AU - Dyrskjøt, Lars

PY - 2021/4/16

Y1 - 2021/4/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85104378401&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-22465-w

DO - 10.1038/s41467-021-22465-w

M3 - Journal article

C2 - 33863885

AN - SCOPUS:85104378401

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2301

ER -

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

Abstract

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