Abstract 5086: Frequent genetic alteration in transitional cell carcinoma of the bladder by large scale exome sequencing

Abstract

Abstract Bladder cancer is the ninth most common cancer worldwide, with TCC being the predominant form (90%). We completed a preliminary research that investigated into exomes of 9 TCCs and target genes of additional TCCs, and discovered frequent aberrations of the chromatin remodeling genes. Six genes, including UTX, MLL/MLL3, CREBBP/EP300, NCOR1, ARID1A and CHD6, were identified in 59% of the 97 TCC patients. Here, in order to obtain a more comprehensive genetic overview of TCC, we sequenced both exomes and whole genomes for another 92 TCC samples. For exome sequencing, we had an average coverage of 75.3x for targeted regions encompassing 38M of Refseq census coding sequence, and >92% of the target bases were covered sufficiently for variant calling (≥10×). As for whole genome resequencing, we achieved the average coverage at 3.8x. We analyzed the exome and genome sequencing data of 92 TCC samples together with the 9 TCCs from the preliminary study to identify the somatic mutations and copy number variations (CNVs), and detected 11,143 non-sysnonymous point mutations, 1,041 small Indels in coding regions (<100bp) and 12,034 CNVs. A total of 12,216 genes were found to be affected by these somatic genetic changes. Furthermore, 125 genes that harbored the confirmed non-silent mutations in at least five other tumors types were observed to have a significantly higher (likelihood test, p<0.01) non-silent mutation rate than the background. We also analyzed the biological pathways by Gene Set Enrichment Analysis, and discovered that the MAPK signaling pathway and the pathway of actin cytoskeleton regulation were mutated in 76 and 75 TCC tumor samples, respectively. Our studies gathered a large number of genetic data on Bladder cancer by applying exome and whole genome sequencing, and provided an unprecedented panoramic view of the genetic basis of TCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5086. doi:1538-7445.AM2012-5086