• Major finding: Genes encoding chromatin-modifying proteins are frequently mutated in bladder cancer.

  • Impact: Comprehensive analysis of TCC reveals new bladder cancer genes.

  • Clinical relevance: Epigenetic-based therapies may be useful in treatment of TCC.

The vast majority of bladder cancers are transitional cell carcinomas (TCC), which arise from the transitional epithelium of the urogenital tract. TCCs are known to harbor mutations in TP53, RB1, FGFR3, HRAS, and KRAS, but this cancer has not been systematically analyzed. Gui and colleagues performed whole-exome sequencing of genomic DNA from 9 high-grade TCC patient samples and matched peripheral blood. The coding sequences of mutated genes were then analyzed in a panel of 51 high-grade and 37 low-grade TCCs, identifying 54 genes with non-synonymous mutations in at least 2 tumors. Frequent mutations in the genes previously linked to TCC were identified, but an unexpected prevalence of mutations in genes involved in chromatin remodeling was also noted. UTX, which encodes a histone demethylase, was mutated as frequently as TP53 in TCC (21% of cases). Interestingly, mutations in UTX were more frequent in low-grade tumors, suggesting that UTX-dependent epigenetic changes may play a role in the initiation of TCC. Two genes encoding histone acetyltransferases, CREBBP and EP300, and ARID1A, encoding a subunit of the SWI/SNF nucleosome remodeling complex, were each mutated in 13% of TCCs, occurring more frequently than RB1, FGFR3, HRAS, or KRAS mutations. Loss-of-function mutations accounted for the majority of these lesions, implicating chromatin-modifying proteins as tumor suppressors in transitional cells. Notably, mutations in ARID1A and another SWI/SNF subunit, PBRM1, have respectively been identified in ovarian and renal clear cell carcinomas, hinting at a broader role of chromatin remodelers in tumor suppression. In total, 59% of TCCs had mutations in a chromatin remodeling gene, indicating that development of these tumors may especially depend on an altered epigenetic landscape. Therapeutic agents that reverse epigenetic modifications may therefore be efficacious in the treatment of bladder cancer.

Gui Y, Guo G, Huang Y, Hu X, Tang A, Gao S, et al. Frequent mutations of chromatin remodeling genes in translational cell carcinoma of the bladder. Nat Genet. 2011 Aug 7. [Epub ahead of print]

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