Genomic characterization of metastatic urothelial carcinoma.

Abstract

247 Background: The genetic profile of primary urothelial carcinoma (UC) has been well documented but no reports analyze specific chromosomal alterations in metastatic disease. We performed molecular inversion probe array (MIP) analysis to compare chromosomal gains or losses in metastatic and primary UC samples. Methods: 33 samples of metastatic UC and 30 primary samples were analyzed from 48 patients (pts), of which paired primary and metastatic tissue was available for 14 pts. DNA from all samples was subjected to molecular inversion probe array analysis to identify focal areas of copy number gain (CNG) or loss (CNL). We focused this analysis on 21 genes from signaling pathways known to be of interest in UC (Table). CNG or CNL was defined as a log2 copy number ratio ≥ 0.8 or ≤ -0.8. GISTIC 2.0 was used to identify significantly altered regions. Results: In the loci analyzed, there were significantly more alterations in metastases than primary samples (8.4% vs 4.3% p=0.002). In particular, there was a significantly higher frequency of E2F3CNG in metastases (27% vs 7% p=0.046). There was frequent discordance in alterations when comparing primary and metastatic tissue from the same patients: 7 of 14 pts harbored potentially oncogenic CNG/CNL in their metastases that were not present in the primary. Conclusions: More alterations in UC-relevant genes were identified in metastases compared with primary tumors, in keeping with the multistep model of cumulative genetic change in cancer progression. More frequent CNG of the E2F3 gene was noted and may represent a mechanism of UC progression. Frequent discordance in alterations between primaries and metastases may be of significant clinical relevance in the future when selecting patients for appropriate molecularly targeted therapy. [Table: see text]