Abstract
BackgroundTo date, there have been no reports characterizing the genome-wide somatic DNA chromosomal copy-number alteration landscape in metastatic urothelial carcinoma. We sought to characterize the DNA copy-number profile in a cohort of metastatic samples and compare them to a cohort of primary urothelial carcinoma samples in order to identify changes that are associated with progression from primary to metastatic disease.MethodsUsing molecular inversion probe array analysis we compared genome-wide chromosomal copy-number alterations between 30 metastatic and 29 primary UC samples. Whole transcriptome RNA-Seq analysis was also performed in primary and matched metastatic samples which was available for 9 patients.ResultsBased on a focused analysis of 32 genes in which alterations may be clinically actionable, there were significantly more amplifications/deletions in metastases (8.6% vs 4.5%, p < 0.001). In particular, there was a higher frequency of E2F3 amplification in metastases (30% vs 7%, p = 0.046). Paired primary and metastatic tissue was available for 11 patients and 3 of these had amplifications of potential clinical relevance in metastases that were not in the primary tumor including ERBB2, CDK4, CCND1, E2F3, and AKT1. The transcriptional activity of these amplifications was supported by RNA expression data.ConclusionsThe discordance in alterations between primary and metastatic tissue may be of clinical relevance in the era of genomically directed precision cancer medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1192-2) contains supplementary material, which is available to authorized users.
Highlights
To date, there have been no reports characterizing the genome-wide somatic DNA chromosomal copy-number alteration landscape in metastatic urothelial carcinoma
We compared the frequency of amplifications and deletions between primary tumors and metastases in these 21 genes as well as another 11 regions found to have statistically significant focal somatic copy-number alterations (SCNAs) in the The Cancer Genome Atlas (TCGA) analysis (Table 2) [3,4,5,6,7,9]
There were more amplifications/deletions in these genes in metastases compared with primary tumors (8.6% loci altered vs. 4.5%, p < 0.001 Fishers exact, Table 2)
Summary
There have been no reports characterizing the genome-wide somatic DNA chromosomal copy-number alteration landscape in metastatic urothelial carcinoma. Extensive data characterizing the genetic profile of primary UC has been published and includes The Cancer Genome Atlas (TCGA) project which comprehensively describes the molecular features of primary muscle-invasive bladder UC [3]. These studies have identified several recurrent and therapeutically targetable genetic alterations but have focused on primary tumor characterization rather than the Bambury et al BMC Cancer (2015) 15:242 tumors [4,6,7,8]. We compared these metastases to primary tumors using SCNA and RNA expression analysis to understand the genetic and transcriptomic differences between these two disease states and to identify changes associated with progression from primary to metastatic disease
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