Concurrent alterations in TERT, KDM6A, and the BRCA pathway in bladder cancer

Nickerson, Michael L., Dancik, Garrett M., Im, Kate M., Edwards, Michael G., Turan, Sevilay, Brown, Joseph, Ruiz-Rodriguez, Christina, Owens, Charles, Costello, James C., Guo, Guangwu, Tsang, Shirley X., Li, Yingrui, Zhou, Quan, Cai, Zhiming, Moore, Lee E., Lucia, M. Scott, Dean, Michael and Theodorescu, Dan (2014) Concurrent alterations in TERT, KDM6A, and the BRCA pathway in bladder cancer. Clinical Cancer Research, 20 18: 4935-4948. doi:10.1158/1078-0432.CCR-14-0330

Author Nickerson, Michael L.
Dancik, Garrett M.
Im, Kate M.
Edwards, Michael G.
Turan, Sevilay
Brown, Joseph
Ruiz-Rodriguez, Christina
Owens, Charles
Costello, James C.
Guo, Guangwu
Tsang, Shirley X.
Li, Yingrui
Zhou, Quan
Cai, Zhiming
Moore, Lee E.
Lucia, M. Scott
Dean, Michael
Theodorescu, Dan
Title Concurrent alterations in TERT, KDM6A, and the BRCA pathway in bladder cancer
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
Publication date 2014-09-15
Year available 2014
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-14-0330
Open Access Status Not Open Access
Volume 20
Issue 18
Start page 4935
End page 4948
Total pages 14
Place of publication Philadelphia, PA United States
Publisher American Association for Cancer Research Inc.
Language eng
Formatted abstract
Purpose: Genetic analysis of bladder cancer has revealed a number of frequently altered genes, including frequent alterations of the telomerase (TERT) gene promoter, although few altered genes have been functionally evaluated. Our objective is to characterize alterations observed by exome sequencing and sequencing of the TERT promoter, and to examine the functional relevance of histone lysine (K)–specific demethylase 6A (KDM6A/UTX), a frequently mutated histone demethylase, in bladder cancer.

Experimental Design: We analyzed bladder cancer samples from 54 U.S. patients by exome and targeted sequencing and confirmed somatic variants using normal tissue from the same patient. We examined the biologic function of KDM6A using in vivo and in vitro assays.

Results: We observed frequent somatic alterations in BRCA1 associated protein-1 (BAP1) in 15% of tumors, including deleterious alterations to the deubiquitinase active site and the nuclear localization signal. BAP1 mutations contribute to a high frequency of tumors with breast cancer (BRCA) DNA repair pathway alterations and were significantly associated with papillary histologic features in tumors. BAP1 and KDM6A mutations significantly co-occurred in tumors. Somatic variants altering the TERT promoter were found in 69% of tumors but were not correlated with alterations in other bladder cancer genes. We examined the function of KDM6A, altered in 24% of tumors, and show depletion in human bladder cancer cells, enhanced in vitro proliferation, in vivo tumor growth, and cell migration.

Conclusions: This study is the first to identify frequent BAP1 and BRCA pathway alterations in bladder cancer, show TERT promoter alterations are independent of other bladder cancer gene alterations, and show KDM6A loss is a driver of the bladder cancer phenotype.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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