Abstract 4702: Genome-wide analysis of copy number alternations and gene mutations in renal cell carcinoma
Authors: Sato Yusuke , Matsubara Aiko , Nagata Yasunobu , Yoshida Kenichi , Sanada Masashi , Kume Haruki , Homma Yukio , Ogawa Seishi 
Published: June 2012

Abstract
Renal cell carcinoma (RCC) is the most common form of adult kidney cancer and accounts for 2-3% of all adult malignancies. The majority of RCC are classified as clear cell RCC. 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. Other molecular pathways may contribute to tumor progression or poor prognosis, but such pathways are still unclear. Known cancer genes frequently mutated in other adult cancers, such as RAS, BRAF, TP53, RB, PIK3CA and EGFR, make only a small contribution to clear cell RCC. To improve clinical outcome, a better understanding of critical genes associated with the pathogenesis of RCC is required.In this study, to obtain a comprehensive registry of critical genetic lesions in RCC, we performed SNP array-based genome-wide copy number analysis for &gt;200 paired RCC specimens as well as whole exome analysis for nucleotide alterations using high-throughout resequencing technologies for selected cases. Copy number alterations were quite common in RCC and 96% of 200 RCC specimens showed one or more copy number changes. These lesions typically involve whole chromosomal arms, whereas focal gains and losses were rare and not recurrent. Recurrent copy number alterations included 3p- (68%) and acquired uniparental disomy (aUPD) of 3p (23%), 5q+ (63%), 7q+ (41%), 9p- (17%), 14q- (27%), which were used for clustering RCC cases into several subgroups with discrete genomic profiles and clinical pictures. Approximately one fourth of RCC cases were hyperploid, which predicted frequent metastatic diseases and poor prognosis. Interestingly, the hyperploid cases showed genomic profiles very similar to those of near diploid cases except for their ploidity, indicating that the hyperploid tumors were derived from the near diploid components. Multivariate analysis revealed several independent predictors of prognosis, where hyperploid and 14q LOH consistently predict poor clinical outcomes. Whole exome analysis was performed for 10 RCC paired specimens by combining SureSelect technologies (Agilent) with high-throughput resequencing using Genome Analizer (Illumina), where tumor specific genetic changes were intensively explored. A large number of tumor-specific nucleotide mutations and insertions/deletions were identified involving PTPRG, ERG, and other genes, which were thought to be involved in RCC pathogenesis and thus to be possible targets for novel therapeutics. In this meeting, we will present the result of our comprehensive genetic analysis of RCC and discuss the genetic basis of RCC in terms of copy number alternations and gene mutations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4702. doi:10.1158/1538-7445.AM2011-4702