Artikel
Proteomic profiling of muscle invasive bladder cancer treated with neoadjuvant chemotherapy reveals unique biologic clusters with clinical relevance
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Autoren
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Moritz Reike
- Klinik für Urologie, Marien Hospital Herne, Ruhr-Universität Bochum, Herne, Germany; Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
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Alberto Contreras-Sanz
- Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
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Gian Negri
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Research Institute, University of British Columbia, Vancouver, Canada
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Htoo Zarni Oo
- Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
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Sandra Spencer Miko
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Research Institute, University of British Columbia, Vancouver, Canada
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Karina Nielsen
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Research Institute, University of British Columbia, Vancouver, Canada
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Morgan E Roberts
- Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
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Joshua Scurll
- Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
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Kenichiro Ikeda
- Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
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Gang Wang
- Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
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Roland Seiler
- Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
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Gregg B. Morin
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Research Institute, University of British Columbia, Vancouver, Canada
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Peter Black
- Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| Veröffentlicht: | 28. März 2023 |
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Gliederung
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Einleitung: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is recommended for muscle invasive bladder cancer (MIBC). However, only ~40% of patients show an objective response. While DNA alterations and RNA classifiers may predict response to NAC in retrospective studies, the proteome has not been evaluated in this context. Here we profile the MIBC proteome in a NAC-treated cohort to identify markers of response and to elucidate mechanisms of resistance to NAC.
Methode: Pre-NAC tissue was included from 107 MIBC patients who received NAC followed by RC. Residual tumor (≥ ypT1N0-3M0-1) in the RC specimen was present in 62% of patients after NAC, and was profiled for 55 of those patients (51%). Benign ureter was used as control. SP3-Clinical Tissue Proteomics (SP3-CTP) and bioinformatic analysis using formalin-fixed paraffin-embedded tissue (FFPE) were performed. Immunohistochemistry (IHC) validation was conducted on matched tissues.
Ergebnisse: We quantified 9,769 proteins across all samples. Unsupervised clustering of pre-NAC tissue established 4 clusters based on biology and survival outcomes, but no difference in response by pathologic stage. Clusters were confirmed by IHC, and consisted of: Cluster 1 (CC1), with high metabolic activity and a luminal profile; Cluster 2 (CC2) with high nuclear activity; Cluster 3 (CC3) with high immune infiltration and basal profile; and Cluster (CC4) with high immune infiltration and stromal signature. CC3 showed worse survival outcomes (p<0.01). Multivariable analysis identified novel favorable (MAPK9 and MTIF3) and unfavorable (DVL2 and NES) biomarkers. Matched analysis of pre- and post-NAC tissue showed markers (AZGP1 and ORM1) and pathways indicative of NAC resistance. In post-NAC (i.e. resistant) tumors we identified 2 clusters: Post-NAC Cluster 1 was enriched for nuclear processes and had worse outcomes, whereas Post-NAC Cluster 2 was enriched for immune pathways.
Schlussfolgerung: Here we describe 4 pre-NAC and 2 post-NAC proteomic clusters with distinct biology and survival outcomes, alongside novel prognostic biomarkers. Future work includes IHC validation of clusters in larger independent MIBC cohorts. A non-NAC cohort using pre-RC biopsy tissue will be used to confirm the prognostic vs. predictive relevance of these findings.
