PS 16. Genomic study on transitional cell carcinoma of the bladder
Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Previous studies based on candidate gene approaches have provided important insights into potential diagnoses and therapeutic applications, yet no comprehensive analysis of this cancer has been performed. In this study, we aimed to screen TCC systematically to identify other novel bladder cancer associated genes by exomic capture and massively parallel sequencing technologies.
The exomes of nine TCC patients were captured with NimbleGen 2.1M Human Exome Arrays and sequenced with Illumina GAII platform. All the somatically mutated genes discovered from the nine patients were screened in a prevalence set of 88 additional TCCs with different tumor stages and grades. The non-silent somatic substitutions and indels were validated by mass spectrum and Sanger sequencing, respectively.
54 significantly mutated genes in the 97 patients were identified. Five genes with well-established roles in TCC showed significantly higher mutation frequency in our study, including TP53 (altered in 21% of TCCs), RB1 (altered in 11%), HRAS (altered in 10%), FGFR3 (altered in 9%), and KRAS (altered in 6%). The other 49 significantly mutated genes were all novel candidates with no previously well-defined roles in TCCs and 33% (16/49) of them were frequently mutated genes which showed mutations in more than 5% of TCCs. Most notably, frequent non-silent mutations in eight genes that were involved in the chromatin remodeling process were detected. Of these genes, the most frequently altered were the histone demethylase gene (HDMT) UTX (mutated in 21% of TCCs); two histone acetyltransferase (HAT) genes CREBBP and EP300, and the SWI/SNF-related chromatin remodeling gene ARID1A (all mutated in 13%). Aberration of each of the remaining four genes was also detected in more than 5% of TCCs, including the histone methyltransferase (HMT) genes MLL and MLL3, and two other chromatin remodeling genes NCOR1 (encoding a constitutive subunit for the N-coR-HDAC3 complex that possesses histone deacetylation (HDAT) activity) and CHD6 (encoding a component of SNF2/RAD54 helicase family that remodels chromatin to allow cell-type specific gene expression). The genetic aberrations of the eight chromatin remodeling genes (UTX, MLL/MLL3, CREBBP/EP300, NCOR1, ARID1A and CHD6) were identified in 59% of 97 TCC patients. Of these genes, UTX was shown to be altered significantly more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer.
These results provided an overview of the genetic basis of TCC and suggested that aberration of chromatin regulation might be a hallmark of bladder cancer.
