Integrative Analysis of 1q23.3 Copy-Number Gain in Metastatic Urothelial Carcinoma

Abstract

Purpose Metastatic urothelial carcinoma (UC) 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 UC treated with platinum-based chemotherapy. Experimental Design We obtained overall survival (OS) and array DNA copy number data from metastatic UC patients 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 was 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 the both cohorts (adjusted HR 2.96; 95% CI, 1.35 to 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 UC. 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 poor risk UC patients. Prospective validation of the survival association is necessary to demonstrate clinical relevance.

RETRACTED: Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer

“…We used transcriptomic profiles of patients with BLCA from publicly available data sets: Riester [22, 23]; Vallot [24]; Kim [25]; Lindgren [26]; and The Cancer Genome Atlas (TCGA) (Supplementary Figure 2). We generated transcriptomic signatures of BLCA in smoker and non-smoker patients using the Riester and TCGA data sets.…”

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Analysis of Argonaute Complex Bound mRNAs in DU145 Prostate Carcinoma Cells Reveals New miRNA Target Genes

“…However, overexpression of DEDD was observed in HP16/18 transformed cervical carcinoma cells [52]. Also copy number gain of 1q23.3 which included amplification of DEDD in urothelial tumors was recently described [53] as well as increased DEDD expression in nasopharyngeal carcinoma [54]. A function for DEDD in transcriptional activation via NFKB in addition to its role in apoptosis has been described [55].…”