Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent mutations of UNC5C and prognostic importance of DNA repair gene mutations on survival

Abstract

Purpose: Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators.

Experimental design: Using pTN staging, we case-matched 81 patients with resected ≥pT2 bladder cancers for whom perioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients.

Results: We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patients who were carriers of somatic mutations in DNA repair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P = 0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n = 25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22-0.98; P = 0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage.

Conclusion: Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted.

©2014 American Association for Cancer Research.

Figures

Figure 1

The significantly mutated genes derived from both Genome MuSic and MutSigCV algorithms were represented in this figure. In the top panel, a graphical representation of the number and type of somatic mutations observed in the significantly mutated genes of each sample was presented. The frequencies (% of analyzed samples) of mutations in each gene are depicted in the bar graph on the left and −log10(p-value) is shown on the right panel.

Figure 2

Schematic representation of the UNC5C gene indicating exon-intron regions and the nucleotide and amino acid location of the somatic mutations observed.

Figure 3

A. Frequencies of mutations in each DNA repair gene detected in our panel of bladder carcinoma patients in relationship to status of recurrence and adjuvant chemotherapy. B. Kaplan-Meier analysis of the effect of mutations in DNA repair genes on recurrence-free survival. A blue line denotes carriers of mutations in DNA repair genes (n=25). A black line denotes non-carriers of mutations in DNA repair genes (n=54). The open circle markers on survival curves are censored cases.