Amplification of chromosome 3q21-25 in urothelial carcinoma with squamous differentiation.

Abstract

457 Background: Squamous differentiation is found in up to 60% of patients with urothelial carcinoma of the bladder. There is conflicting evidence regarding clinical relevance of aberrant urothelial differentiation as both population-based and retrospective studies have supported and refuted its correlation with poor prognosis and advanced stage in multivariate models. The biology of these tumors is poorly understood but some suggest that extensive squamous differentiation may resemble pure squamous tumors with similar responses to chemotherapy, radiation, and higher rate of local recurrence. Our aim was to compare tumors with squamous differentiation with those of pure urothelial histology at the genomic level to better elucidate targetable differences. Methods: We reviewed pathology reports for 412 patients with urothelial carcinoma from TCGA to identify patients with any amount squamous differentiation. Copy number alteration data obtained via the GISTC algorithm was downloaded from cbioportal.com. Chi square analysis was used to compare chromosomal amplifications in samples with squamous differentiation compared with samples that had no amount of variant histology. Results: 50 patients (12%) had some squamous differentiation, of which 15 commented on the percent of involvement – on average, 17% of the sample had squamous differentiation. A total of 257 (62%) of patients had no variant histology. Multiple specific sites in the 3q21-26 chromosomal region were noted to be amplified in squamous histology compared with pure urothelial carcinoma. Specific genes found to be amplified included SOX2 and PIK3. Conclusions: Amplifications of chromosome 3q21-25 were enriched in patients with squamous differentiation compared to those with pure urothelial carcinoma of the bladder. Amplification of this region has been reported in squamous transformation in multiple sites, including lung cancer. This study shows that, similar to other cancers, SOX2 may be necessary for squamous transformation. Furthermore, squamous cancer, which has traditionally though to be chemo-resistant, may respond to agents that target amplifications of genes found on the long arm of chromosome 3 including the PIK3-Akt pathway.