Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

Abstract

Topoisomerase genes were analyzed at both DNA and RNA levels in 25 cases of newly diagnosed childhood acute lymphoblastic leukemia (ALL). The results of molecular analysis were compared to risk group classification of children in order to identify molecular characteristics associated with response to therapy. At diagnosis, allelic imbalance at topoisomerase IIa (TOP2A) gene locus was found in 75% of informative cases whereas topoisomerase I and IIb gene loci are altered in none or only one case, respectively. By semiquantitative Polymerase chain reaction, we found a 2.5 to 8-fold TOP2A gene amplification in 72% of the children, which was correlated to gene overexpression in every case. These results show that TOP2A gene amplification is a frequent event in ALL at diagnosis. Interestingly, we also identified a small population of children that do not present TOP2A gene amplification or gene overexpression and who are significantly associated with very high risk classified patients showing glucocorticoid resistance. In conclusion, characterization of TOP2A gene status in childhood ALL at diagnosis provides useful complementary information for risk assessment.

The incidence of topoisomerase II-alpha genomic alterations in adenocarcinoma of the breast and their relationship to human epidermal growth factor receptor-2 gene amplification: A fluorescence in situ hybridization study

“…In addition, data from other types of cancers support the notion that TOP2A genomic alterations are more prevalent that previously thought and can occur independent of HER2 amplification. In both gastric cancer [33] and lung cancer [34], the data suggest that TOP2A amplifications are more common than HER2 amplification, and isolated TOP2A amplifications have also been reported in acute lymphoblastic leukemias [35] and in carcinomas of the urinary bladder [36]. The exact mechanism whereby HER2 amplification leads to TOP2A gene aberrations remains unclear [20].…”

A set of genes that regulate cell proliferation predicts treatment outcome in childhood acute lymphoblastic leukemia

“…For example, our result that lower expression of TOP2A, the target of daunorubicin activity, is associated with positive MRD and a higher risk of leukemic relapse agrees well with the report that a decrease in TOP2A expression in a leukemia cell line caused a reduction in sensitivity to daunorubicin. 29 In addition, low TOP2A expression was associated with an inferior outcome in breast cancer patients receiving anthracyclins 30,31 and with high-risk features in childhood ALL, 32 although no significant relation was found between TOP2A expression and in vitro resistance to daunorubicin and teniposide in diagnostic and relapsed childhood ALL samples. 33 BUB3, MAD2L1, and NUSAP1, which participate in mitotic spindle assembly, were all expressed at lower levels in patients with MRD and an inferior outcome in our study, consistent with the spindle poison activity of vincristine.…”

Mining expression and prognosis of topoisomerase isoforms in non-small-cell lung cancer by using Oncomine and Kaplan–Meier plotter

“…To a certain extent, the expression level of TOP2A reflects the proliferation status of tumors. The high expression of TOP2A in tumor tissue predicted poor prognosis in some tumor patients [28, 54–56] and also promoted lymph node metastasis and distant metastasis in malignant tumors [29, 57]. There was not a statistically significant association of TOP2A expression with clinical parameters, such as age, gender or pathological tumor stage [30, 31].…”