Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder

Abstract

Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.

Figure 1

Somatic mutations in UTX, ARID1A and CREBBP-EP300. The types and relative positions of confirmed somatic mutations are shown in the transcripts of UTX (a), ARID1A (b) and CREBBP-EP300 (c) using the following symbols: red stars, nonsense mutations; bullets, missense mutations; red triangles, frame-shift indels; green triangles, in-frame indels; and diamond, mutations at splice sites. Domains and motifs in each encoded protein product, as well as the key region responsible for the histone acetyltransferase activity of CREBBP, are also indicated. TPR, tetratricopeptide repeat; JmjC, transcription factor jumonji/aspartyl beta-hydroxylase; ARID, AT-rich interactive domain; LXXLL, C-terminal leucine-rich LXXLL motif; CH1, CH2 and CH3, cysteine–histidine-rich domains; KIX, CREB-binding domain; Bromo, bromodomain.

Figure 2

Concurrent and mutually exclusive mutations observed in the frequently mutated genes. For each gene (row) indicated, tumors (columns) with or without mutations are labeled in red or blue, respectively. P values for the occurrence of concurrent and mutual exclusive mutations in two genes across tumors are provided in Supplementary Table 8. We selected only genes harboring non-silent mutations in at least five subjects for this analysis.

Figure 3

Frequencies of mutations in highlighted genes across different tumor stages and grades. T, the stage of tumors under the TNM (tumor, lymph node and distant metastasis) classification system; G, grade of tumors. For each tumor stage or grade, we calculated the frequency of mutations in a given gene as the proportion of tumors harboring no silent mutations in the gene among all tumors of the indicated stage or grade. We determined the significance of the correlation between mutations in each gene (altered in at least 10% of TCCs) and tumor grade or stage using χ² tests.