Topoisomerase II α Status in Renal Medullary Carcinoma: Immuno-Expression and Gene Copy Alterations of a Potential Target of Therapy

No AccessJournal of UrologyInvestigative Urology1 Aug 2009Topoisomerase II α Status in Renal Medullary Carcinoma: Immuno-Expression and Gene Copy Alterations of a Potential Target of Therapyis companion ofAge at Diagnosis is an Independent Predictor of Small Renal Cell Carcinoma Recurrence-Free Survival Roula Albadine, Wenle Wang, Noel A. Brownlee, Antoun Toubaji, Athanase Billis, Perdram Argani, Jonathan I. Epstein, A. Julian Garvin, Rima Cousi, Edward M. Schaeffer, Christian Pavlovich, and George J. Netto Roula AlbadineRoula Albadine Department of Pathology, Johns Hopkins University, Baltimore, Maryland More articles by this author , Wenle WangWenle Wang Department of Pathology, Johns Hopkins University, Baltimore, Maryland More articles by this author , Noel A. BrownleeNoel A. Brownlee Department of Pathology, Johns Hopkins University, Baltimore, Maryland More articles by this author , Antoun ToubajiAntoun Toubaji Department of Pathology, Johns Hopkins University, Baltimore, Maryland More articles by this author , Athanase BillisAthanase Billis University of Campinas, São Paolo, Brazil More articles by this author , Perdram ArganiPerdram Argani Department of Pathology, Johns Hopkins University, Baltimore, Maryland More articles by this author , Jonathan I. EpsteinJonathan I. Epstein Johns Hopkins University, Baltimore, Maryland More articles by this author , A. Julian GarvinA. Julian Garvin Department of Pathology, Wake Forest University, Winston-Salem, North Carolina More articles by this author , Rima CousiRima Cousi Department of Oncology, Johns Hopkins University, Baltimore, Maryland More articles by this author , Edward M. SchaefferEdward M. Schaeffer Department of Urology, Johns Hopkins University, Baltimore, Maryland More articles by this author , Christian PavlovichChristian Pavlovich Department of Urology, Johns Hopkins University, Baltimore, Maryland More articles by this author , and George J. NettoGeorge J. Netto Johns Hopkins University, Baltimore, Maryland More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2009.03.078AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Renal medullary carcinoma is an aggressive renal neoplasm without currently available effective therapy to our knowledge. Topoisomerase II α is a gyrase involved in cell proliferation, and DNA maintenance and repair. Topoisomerase II α is a target of inhibiting agents such as anthracyclines. Triggered by a recent response to topoisomerase II α inhibitors in a patient with renal medullary carcinoma, we evaluated topoisomerase II α expression in relation to the proliferation index and topoisomerase II α gene copy number status in a larger series of patients with renal medullary carcinoma. Materials and Methods: Archival tissues from 14 renal medullary carcinomas were retrieved from our 3 institutions. Immunohistochemistry was performed using monoclonal antibodies for topoisomerase II α and Ki67. The percent of cells with positive nuclear staining was assessed in the highest area of expression for each marker. A previously suggested greater than 5% cutoff was used for topoisomerase II α over expression. The topoisomerase II α gene copy number was evaluated using fluorescence in situ hybridization. Locus specific topoisomerase II α gene and chromosome 17 centromere probes were used. The total number of topoisomerase II α and chromosome 17 centromere signals was counted in 150 cells per tumor and a topoisomerase II α-to-chromosome 17 centromere signal ratio was calculated in each tumor. A topoisomerase II α-to-chromosome 17 centromere ratio of 2.0 or greater and less than 0.8 was used as a cutoff for amplification and deletion, respectively. The percent of tumor cells with polysomic, eusomic or monosomic chromosome 17 status was also determined. Results: On immuno-expression analysis topoisomerase II α immunohistochemistry was technically inconclusive in 1 renal medullary carcinoma. Topoisomerase II α was over expressed in 11 of 13 renal medullary carcinomas (85%) (median 50%, range 1% to 80%). As expected, a high Ki67 proliferation index was noted in 13 of 14 tumors (median 87.5%, range 2% to 100%). Ki67 expression was greater than topoisomerase II α expression in all 13 informative tumors. A strong, statistically significant correlation was found for topoisomerase II α and Ki67 expression (pairwise CC 0.9, p = 0.0000). Topoisomerase II α over expression was associated with shorter survival (p = 0.000). On fluorescence in situ hybridization no topoisomerase II α amplification was detected in any of the 14 renal medullary carcinomas, including the 11 with topoisomerase II α over expression. Topoisomerase II α gene deletions were noted in 4 tumors. Two of 4 deletions were associated with chromosome 17 monosomy and 2 were in eusomic chromosome 17 tumors. Conclusions: Topoisomerase II α is over expressed in 85% of renal medullary carcinomas, potentially supporting the use of topoisomerase II α inhibitor agents to treat this aggressive renal tumor. Our findings suggest that topoisomerase II α over expression in our renal medullary carcinoma cohort was not due to gene amplification, but rather to transcriptional or post-transcriptional modifications. 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Google Scholar © 2009 by American Urological AssociationFiguresReferencesRelatedDetailsRelated articlesJournal of Urology15 Jun 2009Age at Diagnosis is an Independent Predictor of Small Renal Cell Carcinoma Recurrence-Free Survival Volume 182Issue 2August 2009Page: 735-740 Advertisement Copyright & Permissions© 2009 by American Urological AssociationKeywordscarcinomaDNA topoisomerase II alphakidney medullagene deletionkidneyMetricsAuthor Information Roula Albadine Department of Pathology, Johns Hopkins University, Baltimore, Maryland More articles by this author Wenle Wang Department of Pathology, Johns Hopkins University, Baltimore, Maryland More articles by this author Noel A. Brownlee Department of Pathology, Johns Hopkins University, Baltimore, Maryland More articles by this author Antoun Toubaji Department of Pathology, Johns Hopkins University, Baltimore, Maryland More articles by this author Athanase Billis University of Campinas, São Paolo, Brazil More articles by this author Perdram Argani Department of Pathology, Johns Hopkins University, Baltimore, Maryland More articles by this author Jonathan I. Epstein Johns Hopkins University, Baltimore, Maryland More articles by this author A. Julian Garvin Department of Pathology, Wake Forest University, Winston-Salem, North Carolina More articles by this author Rima Cousi Department of Oncology, Johns Hopkins University, Baltimore, Maryland More articles by this author Edward M. Schaeffer Department of Urology, Johns Hopkins University, Baltimore, Maryland More articles by this author Christian Pavlovich Department of Urology, Johns Hopkins University, Baltimore, Maryland More articles by this author George J. Netto Johns Hopkins University, Baltimore, Maryland More articles by this author Expand All Advertisement PDF downloadLoading ...