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

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.

• Authors: Michael L Nickerson, Garrett M Dancik, Kate M Im, Michael G Edwards, Sevilay Turan, Joseph Brown, Christina Ruiz-Rodriguez, Charles Owens, James C Costello, Guangwu Guo, Shirley X Tsang, Yingrui Li, Quan Zhou, Zhiming Cai, Lee E Moore, M Scott Lucia, Michael Dean, Dan Theodorescu
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 18 Pg. 4935-48 (Sep 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 25225064 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• BAP1 protein, human
• BRCA1 Protein
• Nuclear Proteins
• Tumor Suppressor Proteins
• Histone Demethylases
• KDM6A protein, human
• TERT protein, human
• Telomerase
• Ubiquitin Thiolesterase

Topics

• BRCA1 Protein (genetics)
• Carcinoma, Transitional Cell (genetics, metabolism, pathology)
• Histone Demethylases (genetics)
• Humans
• Mutation
• Nuclear Proteins (genetics)
• Telomerase (genetics)
• Transcriptome
• Tumor Suppressor Proteins (genetics)
• Ubiquitin Thiolesterase (genetics)
• Urinary Bladder Neoplasms (genetics, metabolism, pathology)