Morphologic and genomic characterization of urothelial to sarcomatoid transition in muscle-invasive bladder cancer.

Genitsch, Vera; Kollár, Attila; Vandekerkhove, Gillian; Blarer, Jennifer; Furrer, Marc; Annala, Matti; Herberts, Cameron; Pycha, Armin; de Jong, Joep J; Liu, Yang; Krentel, Friedemann; Davicioni, Elai; Wyatt, Alexander W; Gibb, Ewan A; Kruithof-de Julio, Marianna; Seiler, Roland (2019). Morphologic and genomic characterization of urothelial to sarcomatoid transition in muscle-invasive bladder cancer. Urologic oncology - seminars and original investigations, 37(11), pp. 826-836. Elsevier 10.1016/j.urolonc.2019.09.025

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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.

Item Type:

Journal Article (Review Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Urology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Genitsch Gratwohl, Vera; Kollár, Attila; Blarer, Jennifer; Furrer, Marc; Kruithof-de Julio, Marianna and Seiler, Roland

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1078-1439

Publisher:

Elsevier

Language:

English

Submitter:

Vera Genitsch Gratwohl

Date Deposited:

21 Nov 2019 14:11

Last Modified:

21 Nov 2019 14:18

Publisher DOI:

10.1016/j.urolonc.2019.09.025

PubMed ID:

31585777

Uncontrolled Keywords:

Epithelial-to-mesenchymal transition Molecular subtypes Muscle-invasive bladder cancer Sarcomatoid variant

BORIS DOI:

10.7892/boris.134693

URI:

https://boris.unibe.ch/id/eprint/134693

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