Somatic genomic alterations in urothelial cancer: Results of the Cancer Genome Atlas (TCGA) bladder cancer (BC) analysis.

Abstract

285 Background: We report here an integrated analysis of mutation and somatic copy number alterations (SCNAs) in 131 BCs to provide a comprehensive landscape of molecular alterations. Methods: Exon capture, whole exome sequencing (WES), and SNP arrays were performed on 131 MIBCs with no prior chemotherapy treatment, analyzed using the Cancer Genome Atlas Firehose Pipeline, and validated using orthogonal methods. Significantly mutated genes (SMGs) were determined by MutSig v1.5. Recurrent SCNAs were identified via GISTIC 2.0. Consensus non-negative matrix factorization (CNMF) was used to identify SCNA and SMG clusters. Results: 32 genes showed statistically significant levels of recurrent somatic mutation. Known druggable SMGs included FGFR3 (12%), PIK3CA (20%), TSC1 (8%), and ERBB3 (11%). CDKN1A (14%), ERCC2 (12%), RXRA (9%), ELF3 (8%), KLF5 (8%), FOXQ1 (5%), RHOB (5%), PAIP1 (5%), and BTG2 (5%) were not previously reported as SMGs in any other TCGA cancer type. Truncating mutations in 4 SMGs involved in epigenetic regulation (MLL2, ARID1A, KDM6A, and EP300) were significantly enriched. Clustering of both SMGs and focal SNCAs in 125 samples identified three distinct groups. Group A is highly enriched in focal SCNAs in several genes, as well as mutations in MLL2. Group B is enriched in papillary histology, loss of CDKN2A, and alterations in FGFR3. Group C has TP53 mutations, enrichment with RB1 mutations, and amplifications of E2F3 and CCNE1. There were no statistically significant associations between smoking status and the mutational spectrum, frequency of mutation in any SMG, focal SCNAs, or CNMF subtype. Conclusions: Analyses identified potential therapeutic targets in 69% of BCs, including 42% with targets in the PI3K/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Clustering reveals 3 groups with differences in pattern of genomic alteration suggesting the possibility of different pathogenic mechanisms of BC development. Epigenetic regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date, suggesting the future possibility of targeted therapy for chromatin abnormalities.