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Amplification and Overexpression of CACNA1E Correlates with Relapse in Favorable Histology Wilms' Tumors

Authors' Affiliations: ¹ Paediatric Oncology, Institute of Cancer Research/Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom; ² The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom; ³ Departments of Pediatrics and Oncology, University of Alberta, Edmonton, Alberta, Canada; ⁴ Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee; ⁵ Institute of Neurophysiology and Center of Molecular Medicine Cologne, University of Cologne, Cologne, Germany; and ⁶ Department of Pathology, University Hospital of Wales, Cardiff, United Kingdom

Requests for reprints: Chris Jones, Paediatric Oncology, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom. Phone: 44-20-8722-4416; Fax: 44-20-8722-4321; E-mail: chris.jones{at}icr.ac.uk.

Purpose: The most well established molecular markers of poor outcome in Wilms' tumor are loss of heterozygosity at chromosomes 1p and/or 16q, although to date no specific genes at these loci have been identified. We have previously shown a link between genomic gain of chromosome 1q and tumor relapse and sought to further elucidate the role of genes on 1q in treatment failure.

Experimental Design: Microarray-based comparative genomic hybridization identified a microamplification harboring a single gene (CACNA1E) at 1q25.3 in 6 of 76 (7.9%) Wilms' tumors, correlating with a shorter relapse-free survival (P = 0.0044, log-rank test). Further characterization of this gene was carried out by measuring mRNA and protein expression as well as stable transfection of HEK293 cells.

Results: Overexpression of the CACNA1E transcript was associated with DNA copy number (P = 0.0204, ANOVA) and tumor relapse (P = 0.0851, log-rank test). Immunohistochemistry against the protein product Ca_V2.3 revealed expression localized to the apical membrane in the distal tubules of normal kidney but not to the metanephric blastemal cells of fetal kidney from which Wilms' tumors arise. Nuclear localization in 99 of 160 (61.9%) Wilms' tumor cases correlated with a reduced relapse-free survival, particularly in cases treated with preoperative chemotherapy (P = 0.009, log-rank test). Expression profiling of stably transfected HEK293 cells revealed specific up-regulation of the immediate early response genes EGR1/EGR2/EGR3 and FOS/FOSB, mediated by activation of the MEK/ERK5/Nur77 pathway.

Conclusions: These data identify a unique genetic aberration with direct clinical relevance in Wilms' tumor relapse and provide evidence for a potential novel mechanism of treatment resistance in these tumors.