Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Charles C. Guo; Tadeusz Majewski; Li Zhang; Hui Yao; Jolanta Bondaruk; Yan Wang; Shizhen Zhang; Ziqiao Wang; June Goo Lee; Sangkyou Lee; David Cogdell; Miao Zhang; Peng Wei; H. Barton Grossman; Ashish Kamat; Jonathan James Duplisea; James Edward Ferguson; He Huang; Vipulkumar Dadhania; Jianjun Gao; Colin Dinney; John N. Weinstein; Keith Baggerly; David McConkey; Bogdan Czerniak

doi:10.1016/j.celrep.2019.04.048

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Charles C. Guo, Tadeusz Majewski, Li Zhang, Hui Yao, Jolanta Bondaruk, Yan Wang, Shizhen Zhang, Ziqiao Wang, June Goo Lee, Sangkyou Lee, David Cogdell, Miao Zhang, Peng Wei, H. Barton Grossman, Ashish Kamat, Jonathan James Duplisea, James Edward Ferguson, He Huang, Vipulkumar Dadhania, Jianjun GaoColin Dinney, John N. Weinstein, Keith Baggerly, David McConkey, Bogdan Czerniak

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

Abstract

Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer. Guo et al. report that sarcomatoid carcinoma of the bladder evolves by the progression of the basal subtype of conventional urothelial carcinoma with the enrichment of mutagenesis signature 1 and mutations of TP53, RB1, and PIK3CA. It is driven by the dysregulation of the EMT network and shows increased immune infiltrate with overexpression of PD-L1.

Original language	English (US)
Pages (from-to)	1781-1793.e4
Journal	Cell Reports
Volume	27
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2019.04.048
State	Published - May 7 2019

Keywords

basal subtype
bladder cancer
chromatin remodeling
epithelial-mesenchymal transformation
genomic expression
immune phenotype
microRNA expression
molecular classification
sarcomatoid carcinoma
urothelial carcinoma

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Bioinformatics Shared Resource
Biostatistics Resource Group
Tissue Biospecimen and Pathology Resource
Clinical Trials Office

Access to Document

10.1016/j.celrep.2019.04.048

Cite this

Guo, C. C., Majewski, T., Zhang, L., Yao, H., Bondaruk, J., Wang, Y., Zhang, S., Wang, Z., Lee, J. G., Lee, S., Cogdell, D., Zhang, M., Wei, P., Grossman, H. B., Kamat, A., Duplisea, J. J., Ferguson, J. E., Huang, H., Dadhania, V., ... Czerniak, B. (2019). Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer. Cell Reports, 27(6), 1781-1793.e4. https://doi.org/10.1016/j.celrep.2019.04.048

Guo, CC, Majewski, T, Zhang, L, Yao, H, Bondaruk, J, Wang, Y, Zhang, S, Wang, Z, Lee, JG , Lee, S, Cogdell, D, Zhang, M , Wei, P, Grossman, HB, Kamat, A, Duplisea, JJ, Ferguson, JE, Huang, H, Dadhania, V, Gao, J , Dinney, C , Weinstein, JN, Baggerly, K, McConkey, D & Czerniak, B 2019, 'Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer', Cell Reports, vol. 27, no. 6, pp. 1781-1793.e4. https://doi.org/10.1016/j.celrep.2019.04.048

@article{249d3484ab5d4965aeb5eb20bd2a680f,

title = "Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer",

abstract = "Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer. Guo et al. report that sarcomatoid carcinoma of the bladder evolves by the progression of the basal subtype of conventional urothelial carcinoma with the enrichment of mutagenesis signature 1 and mutations of TP53, RB1, and PIK3CA. It is driven by the dysregulation of the EMT network and shows increased immune infiltrate with overexpression of PD-L1.",

keywords = "basal subtype, bladder cancer, chromatin remodeling, epithelial-mesenchymal transformation, genomic expression, immune phenotype, microRNA expression, molecular classification, sarcomatoid carcinoma, urothelial carcinoma",

author = "Guo, {Charles C.} and Tadeusz Majewski and Li Zhang and Hui Yao and Jolanta Bondaruk and Yan Wang and Shizhen Zhang and Ziqiao Wang and Lee, {June Goo} and Sangkyou Lee and David Cogdell and Miao Zhang and Peng Wei and Grossman, {H. Barton} and Ashish Kamat and Duplisea, {Jonathan James} and Ferguson, {James Edward} and He Huang and Vipulkumar Dadhania and Jianjun Gao and Colin Dinney and Weinstein, {John N.} and Keith Baggerly and David McConkey and Bogdan Czerniak",

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = may,

day = "7",

doi = "10.1016/j.celrep.2019.04.048",

language = "English (US)",

volume = "27",

pages = "1781--1793.e4",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

AU - Guo, Charles C.

AU - Majewski, Tadeusz

AU - Zhang, Li

AU - Yao, Hui

AU - Bondaruk, Jolanta

AU - Wang, Yan

AU - Zhang, Shizhen

AU - Wang, Ziqiao

AU - Lee, June Goo

AU - Lee, Sangkyou

AU - Cogdell, David

AU - Zhang, Miao

AU - Wei, Peng

AU - Grossman, H. Barton

AU - Kamat, Ashish

AU - Duplisea, Jonathan James

AU - Ferguson, James Edward

AU - Huang, He

AU - Dadhania, Vipulkumar

AU - Gao, Jianjun

AU - Dinney, Colin

AU - Weinstein, John N.

AU - Baggerly, Keith

AU - McConkey, David

AU - Czerniak, Bogdan

PY - 2019/5/7

Y1 - 2019/5/7

N2 - Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer. Guo et al. report that sarcomatoid carcinoma of the bladder evolves by the progression of the basal subtype of conventional urothelial carcinoma with the enrichment of mutagenesis signature 1 and mutations of TP53, RB1, and PIK3CA. It is driven by the dysregulation of the EMT network and shows increased immune infiltrate with overexpression of PD-L1.

AB - Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer. Guo et al. report that sarcomatoid carcinoma of the bladder evolves by the progression of the basal subtype of conventional urothelial carcinoma with the enrichment of mutagenesis signature 1 and mutations of TP53, RB1, and PIK3CA. It is driven by the dysregulation of the EMT network and shows increased immune infiltrate with overexpression of PD-L1.

KW - basal subtype

KW - bladder cancer

KW - chromatin remodeling

KW - epithelial-mesenchymal transformation

KW - genomic expression

KW - immune phenotype

KW - microRNA expression

KW - molecular classification

KW - sarcomatoid carcinoma

KW - urothelial carcinoma

UR - http://www.scopus.com/inward/record.url?scp=85064861998&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064861998&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.04.048

DO - 10.1016/j.celrep.2019.04.048

M3 - Article

C2 - 31067463

AN - SCOPUS:85064861998

SN - 2211-1247

VL - 27

SP - 1781-1793.e4

JO - Cell Reports

JF - Cell Reports

IS - 6

ER -

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Cite this