Integrative analysis of 1q23.3 copy-number gain in metastatic urothelial carcinoma

Abstract

Purpose: Metastatic urothelial carcinoma of the bladder is associated with multiple somatic copy-number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy.

Experimental design: We obtained overall survival (OS) and array DNA copy-number data from patients with metastatic urothelial carcinoma in two cohorts. Associations between recurrent SCNAs and OS were determined by a Cox proportional hazard model adjusting for performance status and visceral disease. mRNA expression was evaluated for potential candidate genes by NanoString nCounter to identify transcripts from the region that are associated with copy-number gain. In addition, expression data from an independent cohort were used to identify candidate genes.

Results: Multiple areas of recurrent significant gains and losses were identified. Gain of 1q23.3 was independently associated with a shortened OS in both cohorts [adjusted HR, 2.96; 95% confidence interval (CI), 1.35-6.48; P = 0.01 and adjusted HR, 5.03; 95% CI, 1.43-17.73; P < 0.001]. The F11R, PFDN2, PPOX, USP21, and DEDD genes, all located on 1q23.3, were closely associated with poor outcome.

Conclusions: 1q23.3 copy-number gain displayed association with poor survival in two cohorts of metastatic urothelial carcinoma. The identification of the target of this copy-number gain is ongoing, and exploration of this finding in other disease states may be useful for the early identification of patients with poor-risk urothelial carcinoma. Prospective validation of the survival association is necessary to demonstrate clinical relevance.

Figure 1. Recurrent copy number changes

(a) The figure shows recurrent copy number gains and losses in the Spanish (top) and DFCI cohorts (bottom). In panels (b–c), we show hierarchical clustering of the (b) Spanish and (c) DFCI cohort.

Figure 2. Prognostic utility of 1q23.3 amplification

The figure shows the Kaplan-Meier plot for the Spanish cohort (a), DFCI MIP cohort (b). In panel (c), patients of an independent cohort were stratified by the expression median of the PFDN2 gene, located at the peak of the 1q23.3 amplification.

Figure 3. Potential drivers of the 1q23.3 amplification

(a) The figure displays the wide peak amplification regions in three bladder cancer cohorts (Spanish, DFCI and TCGA). Red peak heights visualize the statistical significance (GISTIC q-values). The q-value provides an estimate of the likelihood of the observed copy numbers at the corresponding locus in the cohort; the higher the peak, the higher the probability is that this SCNA has a driver role. The DFCI q-values are lower due to the smaller sample size, not due to a lower prevalence of this peak in this cohort. The GISTIC wide peak regions, defined by the algorithm as regions that likely contain driver genes, are colored in dark red. For the Spanish and DFCI cohorts, the correlation coefficients of gene expression and copy number are plotted in green. Genes with very low or even anti-correlation are unlikely driver genes of 1q23.3 amplification. Blue gene names are known cancer genes (50). Figure S8 provides heatmaps of this region for the Spanish and DFCI cohort. Panel (b) shows the frequency of 1q23.3 amplification in all three cohorts. Peak 1 is marked in black. This plot demonstrates that the frequency of 1q23.3 amplification (log 2 copy number ratio > 0.9) is highest in peak 1.