Vera Genitsch1, Attila Kollár2, Gillian Vandekerkhove3, Jennifer Blarer4, Marc Furrer4, Matti Annala5, Cameron Herberts3, Armin Pycha6, Joep J de Jong7, Yang Liu8, Friedemann Krentel3, Elai Davicioni8, Ewan A Gibb8, Marianna Kruithof-de Julio4, Alexander W Wyatt3, Roland Seiler9. 1. Institute of Pathology, University of Bern, Switzerland. 2. Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland. 3. Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, Canada. 4. Department of Urology, Inselspital, Bern University Hospital, University of Bern, Switzerland. 5. Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, Canada; Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 6. Department of Urology, Central Hospital of Bolzano, Bolzano, Italy. 7. Department of Urology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. 8. GenomeDx Inc., Vancouver, Canada. 9. Department of Urology, Inselspital, Bern University Hospital, University of Bern, Switzerland. Electronic address: r_seiler@gmx.ch.
Abstract
INTRODUCTION: The sarcomatoid morphology of muscle-invasive bladder cancer (MIBC) is associated with unfavorable prognosis. However, the genomic, transcriptomic, and proteomic relationship between conventional urothelial and synchronous sarcomatoid morphology is poorly defined. METHODS: We compiled a cohort of 21 MIBC patients with components of conventional urothelial and adjacent sarcomatoid morphology within the same tumor focus. We performed comprehensive pathologic and immunohistochemical characterization and in 4 selected cases, subjected both morphologic components to targeted DNA sequencing and whole transcriptome analysis. RESULTS: Synchronous sarcomatoid and urothelial morphology from the same MIBC foci shared truncal somatic mutations, indicating a common ancestral clone. However, additional mutations or copy number alterations restricted to the either component suggested divergent evolution at the genomic level. This was confirmed at the transcriptome level since while the urothelial component exhibited a basal-like subtype (TCGA2014: cluster III, LundTax: basal/squamous-like), the sarcomatoid morphology was predominantly cluster IV (claudin-low). Protein expression was consistent with a basal-like phenotype in both morphologies in 18/21 of cases. However, most cases had evidence of active epithelial-to-mesenchymal transition (E-Cad ↓ and Zeb1 or TWIST1 ↑) from urothelial toward the sarcomatoid morphology. Drug response signatures nominated different targets for each morphology and proposed agents under clinical investigation in liposarcoma or other sarcoma. PD-L1 expression was higher in the sarcomatoid than the urothelial component. CONCLUSIONS: Conventional urothelial and adjacent sarcomatoid morphologies of MIBC arise from the same common ancestor and share a basal-like phenotype. However, divergence between the morphologies at the genome, transcriptome, and proteome level suggests differential sensitivity to therapy.
INTRODUCTION: The sarcomatoid morphology of muscle-invasive bladder cancer (MIBC) is associated with unfavorable prognosis. However, the genomic, transcriptomic, and proteomic relationship between conventional urothelial and synchronous sarcomatoid morphology is poorly defined. METHODS: We compiled a cohort of 21 MIBCpatients with components of conventional urothelial and adjacent sarcomatoid morphology within the same tumor focus. We performed comprehensive pathologic and immunohistochemical characterization and in 4 selected cases, subjected both morphologic components to targeted DNA sequencing and whole transcriptome analysis. RESULTS:Synchronous sarcomatoid and urothelial morphology from the same MIBC foci shared truncal somatic mutations, indicating a common ancestral clone. However, additional mutations or copy number alterations restricted to the either component suggested divergent evolution at the genomic level. This was confirmed at the transcriptome level since while the urothelial component exhibited a basal-like subtype (TCGA2014: cluster III, LundTax: basal/squamous-like), the sarcomatoid morphology was predominantly cluster IV (claudin-low). Protein expression was consistent with a basal-like phenotype in both morphologies in 18/21 of cases. However, most cases had evidence of active epithelial-to-mesenchymal transition (E-Cad ↓ and Zeb1 or TWIST1 ↑) from urothelial toward the sarcomatoid morphology. Drug response signatures nominated different targets for each morphology and proposed agents under clinical investigation in liposarcoma or other sarcoma. PD-L1 expression was higher in the sarcomatoid than the urothelial component. CONCLUSIONS: Conventional urothelial and adjacent sarcomatoid morphologies of MIBC arise from the same common ancestor and share a basal-like phenotype. However, divergence between the morphologies at the genome, transcriptome, and proteome level suggests differential sensitivity to therapy.
Authors: Ewan A Gibb; Joaquim Bellmunt; Joep J de Jong; Begoña P Valderrama; Julia Perera; Nuria Juanpere; Paloma Cejas; Henry Long; M Mar Albà Journal: Br J Cancer Date: 2022-04-21 Impact factor: 9.075
Authors: Martina Minoli; Mirjam Kiener; George N Thalmann; Marianna Kruithof-de Julio; Roland Seiler Journal: Int J Mol Sci Date: 2020-08-07 Impact factor: 5.923