Data from Concurrent Alterations in <i>TERT</i>, <i>KDM6A</i>, and the BRCA Pathway in Bladder Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> Genetic analysis of bladder cancer has revealed a number of frequently altered genes, including frequent alterations of the <i>telomerase</i> (<i>TERT</i>) gene promoter, although few altered genes have been functionally evaluated. Our objective is to characterize alterations observed by exome sequencing and sequencing of the <i>TERT</i> promoter, and to examine the functional relevance of <i>histone lysine (K)–specific demethylase 6A</i> (<i>KDM6A/UTX</i>), a frequently mutated histone demethylase, in bladder cancer.</p><p><b>Experimental Design:</b> 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 <i>KDM6A</i> using <i>in vivo</i> and <i>in vitro</i> assays.</p><p><b>Results:</b> We observed frequent somatic alterations in <i>BRCA1 associated protein-1 (BAP1)</i> in 15% of tumors, including deleterious alterations to the deubiquitinase active site and the nuclear localization signal. <i>BAP1</i> 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. <i>BAP1</i> and <i>KDM6A</i> mutations significantly co-occurred in tumors. Somatic variants altering the <i>TERT</i> promoter were found in 69% of tumors but were not correlated with alterations in other bladder cancer genes. We examined the function of <i>KDM6A</i>, altered in 24% of tumors, and show depletion in human bladder cancer cells, enhanced <i>in vitro</i> proliferation, <i>in vivo</i> tumor growth, and cell migration.</p><p><b>Conclusions:</b> This study is the first to identify frequent <i>BAP1</i> and BRCA pathway alterations in bladder cancer, show <i>TERT</i> promoter alterations are independent of other bladder cancer gene alterations, and show <i>KDM6A</i> loss is a driver of the bladder cancer phenotype. <i>Clin Cancer Res; 20(18); 4935–48. ©2014 AACR</i>.</p></div>