You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2012435 GENOME-WIDE ANALYSIS OF COPY NUMBER ALTERATIONS AND GENE MUTATIONS IN RENAL CELL CARCINOMA Yusuke Sato, Shigektsu Maekawa, Aiko Sato, Yasunobu Nagata, Kenichi Yoshida, Yuichi Shiraishi, Tetsukazu Yoshizato, Yusuke Okuno, Hiromichi Suzuki, Masashi Sanada, Haruki Kume, Seishi Ogawa, and Yukio Homma Yusuke SatoYusuke Sato Tokyo, Japan More articles by this author , Shigektsu MaekawaShigektsu Maekawa Tokyo, Japan More articles by this author , Aiko SatoAiko Sato Tokyo, Japan More articles by this author , Yasunobu NagataYasunobu Nagata Tokyo, Japan More articles by this author , Kenichi YoshidaKenichi Yoshida Tokyo, Japan More articles by this author , Yuichi ShiraishiYuichi Shiraishi Tokyo, Japan More articles by this author , Tetsukazu YoshizatoTetsukazu Yoshizato Tokyo, Japan More articles by this author , Yusuke OkunoYusuke Okuno Tokyo, Japan More articles by this author , Hiromichi SuzukiHiromichi Suzuki Tokyo, Japan More articles by this author , Masashi SanadaMasashi Sanada Tokyo, Japan More articles by this author , Haruki KumeHaruki Kume Tokyo, Japan More articles by this author , Seishi OgawaSeishi Ogawa Tokyo, Japan More articles by this author , and Yukio HommaYukio Homma Tokyo, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.502AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Renal cell carcinoma (RCC) is the most common form of adult kidney cancer and accounts for 2-3% of all adult malignancies. The most frequent genetic event in the evolution of clear cell RCC is inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. Advances in our understanding of the VHL pathway of clear cell RCC led to the development of several molecular targeted agents such as tyrosine kinase inhibitors (TKI) and mTOR inhibitors. Nevertheless, patients with metastatic disease still have an extremely short life expectancy. Inactivating mutations of PBRM1 gene were found in 40% of clear cell RCC, but its impact on novel therapeutics is still unclear. To improve clinical outcome, a better understanding of critical genes associated with the pathogenesis of RCC is required. METHODS We performed SNP array-based genome-wide copy number analysis for 250 paired RCC specimens as well as whole exome analysis using high-throughout resequencing technologies for 25 cases. RESULTS Recurrent copy number alterations included 3p− (68%) and acquired uniparental disomy (aUPD) of 3p (23%), 5q+ (63%), 7q+ (41%), 9p− (17%), 14q− (27%). These lesions typically involve whole chromosomal arms, whereas focal gains and losses were rare and not recurrent. Approximately one fifth of RCC cases were hyperploid, which predicted frequent metastatic diseases and poor prognosis. Multivariate analysis revealed hyperploid and 14q LOH were independent predictors of poor prognosis. 42 somatic mutations per sample were identified in whole exome analysis including novel gene mutations which were thought to be involved in clear cell RCC pathogenesis. Among them, mutations of genes involved in chromatin regulation or histone modification were preferentially found in advanced cases. To understand whole picture of gene mutations of epigenetic mechanism in clear cell RCC, mutation analysis of 85 genes involved in chromatin regulation or histone modification were performed in 180 cases using multiplexed barcode sequencing. A total of 201 somatic mutations were validated and 74% cases had at least one somatic mutation. PBRM1 was mutated in 43% cases and had no relation to prognosis. Whereas SETD2 mutation, which was detected in 10% of cases, was associated with the risk of metastasis. CONCLUSIONS Target captured high-throughput resequencing is a powerful method to understand the genetic basis of clear cell RCC. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e178-e179 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yusuke Sato Tokyo, Japan More articles by this author Shigektsu Maekawa Tokyo, Japan More articles by this author Aiko Sato Tokyo, Japan More articles by this author Yasunobu Nagata Tokyo, Japan More articles by this author Kenichi Yoshida Tokyo, Japan More articles by this author Yuichi Shiraishi Tokyo, Japan More articles by this author Tetsukazu Yoshizato Tokyo, Japan More articles by this author Yusuke Okuno Tokyo, Japan More articles by this author Hiromichi Suzuki Tokyo, Japan More articles by this author Masashi Sanada Tokyo, Japan More articles by this author Haruki Kume Tokyo, Japan More articles by this author Seishi Ogawa Tokyo, Japan More articles by this author Yukio Homma Tokyo, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...