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

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 transcription...

Assessment of cell proliferation in renal cell carcinoma using dual-phase 18F-fluorodeoxyglucose PET/CT

“…MCM2 is a superior marker to Ki-67 for assessment of the cell cycle, pathological factors and prognosis in RCC patients (8). Topo II α was reported to be a potential marker of anticancer agent efficacy; in addition, its marked expression in highly malignant RCCs suggests a potential therapeutic use for topo II α inhibitors (9,10).…”

“…Commonly used immunohistochemical cell proliferation markers include Ki-67 antigen, minichromosome maintenance protein 2 (MCM2) and topoisomerase II α (topo II α) (7)(8)(9)(10). The Ki-67 antigen expression is indicative of the proportion of active cells throughout the cell cycle, which makes it an excellent marker for determining the growth fraction of cell populations (7).…”

“…MCM2 is a superior marker to Ki-67 for assessment of the cell cycle, pathological factors and prognosis in RCC patients (8). Topo II α was reported to be a potential marker of anticancer agent efficacy; in addition, its marked expression in highly malignant RCCs suggests a potential therapeutic use for topo II α inhibitors (9,10).Correlations between tumor cell proliferation and 18 F-FDG uptake have been investigated in various malignant tumors (11). However, to the best of our knowledge, the association between tumor cell proliferation and 18 F-FDG uptake in RCC patients remains to be elucidated.…”

Renal Medullary Carcinoma in a White Adolescent With Sickle Cell Trait

“…5,43 A different cohort of RMC patients found an overexpression of topoisomerase IIa protein (TOP2A), a nuclear enzyme that controls DNA topological structure and cell-cycle progression, but not an overexpression of the TOP2A gene, implying not only a possible cause for RMC but also a potential therapeutic role of TOP2A inhibitors. 44 A recent review on the pathogenesis of RMC advocates that there is a common underlying hypoxic cellular environment favoring the activation of a well-known carcinogenetic pathway: the HIF1a. This can arise from conditions that either favor "hypoxia" such as the case of SCT and SCD, or "pseudo-hypoxia" such as the case of genetic mutations such as biallelic inactivation of fumarate hydratase gene or the absence of functional VHL tumorsuppressor protein (von Hippel-Lindau) both of which affect the hypoxia-sensing pathway.…”

Les tumeurs rénales : recommandations de la conférence de consensus de l’International Society of Urologic Pathology (ISUP) 2012

“…Le CM avec ou sans dré-panocytose montre une augmentation de Topo II. Il n'existe pas d'anomalie génétique spécifique [40,41] (Fig. 11 et 12).…”