Brief Correspondence Targeted Exome Sequencing of the Cancer Genome in Patients with Very High-risk Bladder Cancer Thomas Longo a , Kathleen F. McGinley a , Jennifer A. Freedman b , Wiguins Etienne a , Yuan Wu c , Alexander Sibley c , Kouros Owzar c , Jeremy Gresham c , Christopher Moy d , Stephen Szabo e , Joel Greshock f , Hui Zhou e , Yuchen Bai e , Brant A. Inman a, * a Division of Urology, Department of Surgery, Duke University, Durham, NC, USA; b Division of Oncology, Department of Medicine, Duke University, Durham, NC, USA; c Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA; d Janssen Pharmaceuticals Inc., Raritan, NJ, USA; e GlaxoSmithKline, Zebulon, NC, USA; f Novartis, Holly Springs, NC, USA It is essential to discover the genetic drivers of aggressive bladder cancer (BC) to both risk-stratify patients and develop new therapies. The Cancer Genome Atlas (TCGA) Research Network identified several genes involved in cell cycle regulation, chromatin regulation, and kinase signaling pathways that are mutated in BC [1]. However, TCGA used a highly curated cohort of chemotherapy-naı ¨ve, muscle- invasive BCs. Furthermore, few studies have associated specific genetic mutation patterns with particular clinical outcomes [2,3]. In this study, we performed targeted sequencing of the cancer exome in very high-risk BC patients, including patients with nonurothelial histology and who had received chemotherapy, with critical clinical outcomes. We retrospectively identified 50 very high-risk patients chosen for particularly aggressive tumors (very large tumors, positive nodes, metastases, or death). These patients underwent treatment for pTis–pT4b BC between July E U R O P E A N U R O L O G Y X X X ( 2 0 1 6 ) X X X – X X X ava ilable at www.sciencedirect.com journa l homepage: www.europea nurology.com Article info Article history: Accepted July 20, 2016 Associate Editor: James Catto Keywords: Bladder cancer somatic mutations epigenetics IKZF1 GOLGA5 Abstract We completed targeted exome sequencing of the tumors of 50 patients with pTis–pT4b bladder cancer. Mutations were categorized by type, stratified against previously identified cancer loci in the Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas databases, and evaluated in pathway analysis and comutation plots. We analyzed mutation associations with receipt of neoadjuvant chemotherapy, nodal involvement, metastatic disease development, and survival. Compared with The Cancer Genome Atlas, we found higher mutation rates in genes encoding products involved in epigenetic regulation and cell cycle regulation. Of the pathways examined, PI3K/mTOR and Cell Cycle/DNA Repair exhibited the greatest frequencies of mutation. RB1 and TP53, as well as NF1 and PIK3CA were frequently comutated. We identified no association between mutations in specific genes and key clinical outcomes of interest when corrected for multiple testing. Discovery phase analysis of the somatic mutations in 50 high-risk bladder cancer patients revealed novel mutations and mutational patterns, which may be useful for developing targeted therapy regimens or new biomarkers for patients at very high risk of disease metastasis and death. Patient summary: In this report we found known, as well as previously unreported, genetic mutations in the tumors of patients with high-risk bladder cancer. These mutations, if validated, may serve as actionable targets for new trials. # 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Duke University Medical Center, Division of Urology, Box 103868, 3007 Snyderman Building, 905 La Salle Street, Durham, NC 27710, USA. Tel. +1-919-684-1322; Fax: +1-919-668-7093. E-mail address: brant.inman@duke.edu (B.A. Inman). EURURO-6953; No. of Pages 4 Please cite this article in press as: Longo T, et al. Targeted Exome Sequencing of the Cancer Genome in Patients with Very High-risk Bladder Cancer. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.07.049 http://dx.doi.org/10.1016/j.eururo.2016.07.049 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.