Gene Summary

Gene:TOP1; DNA topoisomerase I
Aliases: TOPI
Summary:This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus altering the topology of DNA. This gene is localized to chromosome 20 and has pseudogenes which reside on chromosomes 1 and 22. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA topoisomerase 1
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TOP1 (cancer-related)

Gao Z, Man X, Li Z, et al.
Expression profiles analysis identifies the values of carcinogenesis and the prognostic prediction of three genes in adrenocortical carcinoma.
Oncol Rep. 2019; 41(4):2440-2452 [PubMed] Related Publications
Adrenocortical carcinoma (ACC) is a rare disease associated with a poor prognosis. Furthermore, the underlying molecular mechanism of carcinogenesis is poorly understood, and prognostic prediction of ACC has low accuracy. In the present study, a bioinformatics approach was used to investigate the molecular mechanisms and prognosis of ACC. Samples of adrenal tumors were collected from patients undergoing adrenalectomy at the Department of Urology, the First Hospital of China Medical University. The analyzed gene datasets were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database. Following this, the differentially expressed genes (DEGs) were included in Gene Ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, protein‑protein interaction network and survival analyses. MTT colorimetric assays, colony formation assays and 5‑ethynyl‑20‑deoxyuridine incorporation assays were also conducted to evaluate ACC cell proliferation. The identified DEGs included 20 downregulated genes and 51 upregulated genes, which were highly associated with the cell cycle, organelle fission, chromosome segregation, cell division and spindle stability. The top 14 hub genes were subsequently confirmed by reverse transcription‑quantitative polymerase chain reaction in ACC and adrenocortical adenoma samples. It was identified that the nuclear division cycle 80, cyclin B2 and topoisomerase 2‑α may serve important roles in adrenocortical tumor development. Furthermore, these three genes predicted overall survival and recurrence‑free survival in patients with ACC from the TCGA cohort. The findings identified three novel genes that have important roles in carcinogenesis and in the prognostic prediction of ACC.

Niotis A, Tsiambas E, Fotiades PP, et al.
ki-67 and Topoisomerase IIa proliferation markers in colon adenocarcinoma.
J BUON. 2018; 23(7):24-27 [PubMed] Related Publications
Aberrant cell proliferation is a major cause in the development and progression of carcinogenic process. Epithelia characterized by increased mitotic rates accumulate easily gross numerical and structural chromosomes (polysomy/aneuploidy) and specific gene (deletions, amplifications, point mutations, translocations) deregulations that lead to their progressive neoplastic and finally malignant transformation. Molecules that are critical for evaluating the proliferation status of the corresponding tissues include mainly ki-67 (cytogenetic band: 10q26.2), and also Topoisomerase IIa/Topo IIa (cytogenetic band: 17q21.2). Both of them demonstrate different expression patterns in every cell cycle phase and their estimated expression as Nuclear Labeling Index (NLI) is a very useful tool for assessing the aggressiveness of the examined pre- and malignant tissues. In fact, ki-67 expression increases as a cell progresses through the cell cycle, with highest expression being seen in G2/M phase cell, whereas Topo IIa is expressed in proliferating cells in the late S phase with a peak in G2-M phases. Concerning colon adenocarcinoma, high expression levels of them seem to correlate with advanced disease and also with modified response rates to specific chemotherapeutic agents, such as doxorubicin, an inhibitor of Topo IIa. In the current molecular review we explored the role of these proliferative markers in colon adenocarcinoma and their influence in the tumor biological behavior.

Baechler SA, Factor VM, Dalla Rosa I, et al.
The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis.
Nat Commun. 2019; 10(1):83 [PubMed] Free Access to Full Article Related Publications
Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt-KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies.

Eltohamy MI, Badawy OM, El kinaai N, et al.
Topoisomerase II α Gene alteration in Triple Negative Breast Cancer and Its Predictive Role for Anthracycline-Based Chemotherapy (Egyptian NCI Patients)
Asian Pac J Cancer Prev. 2018; 19(12):3581-3589 [PubMed] Free Access to Full Article Related Publications
Objective: Triple negative breast cancer is an aggressive variant of breast cancer; it forms about 15% of breast cancer cases. It lacks the responsiveness to hormonal and targeted therapies. Anthracyclines remain the treatment option for these patients. Anthracyclines are cardiotoxic, so predicting sensitivity of response by biological predictors may have a role in selecting suitable candidates for these drugs. Material and methods: This study included 50 TNBC cases, from National Cancer Institute, Cairo University(NCI-CU), Egypt, who underwent surgery and received adjuvant chemotherapy. Archived blocks were obtained and immunostaining for Ki-67 LI and Fluorescent In situ Hybridization (FISH) technique to assess TOP2A gene copy number and chromosome 17CEP status were done. Analysis of association between TOP2A alterations and CEP17 polysomy as well as Ki-67 LI with other clinicopathological parameters was done. Associations between the biological markers and event free survival (EFS) and overall survival (OS), were also performed. Results: TOP2A alteration was seen in 9/50 cases (5 amplified and 4 deleted). CEP17 Polysomy was detected in 14% of cases. Most of patients (80%) showed Ki-67 LI ≥20%. There was a significant association between TOP2A gene and CEP17 status. Outcome was better with abnormal TOP2A gene status and CEP17 polysomy, radiotherapy and combined anthracyclines and taxanes in the adjuvant setting, however P-values were not significant. Conclusion: TOP2A gene alterations and CEP17 polysomy may have prognostic and predictive role in TNBC treated with adjuvant Anthracyclines.

Song J, Ma Q, Hu M, et al.
The Inhibition of miR-144-3p on Cell Proliferation and Metastasis by Targeting TOP2A in HCMV-Positive Glioblastoma Cells.
Molecules. 2018; 23(12) [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM), the most common type of primary tumor in the central nervous system, is a very aggressive brain tumor with poor prognosis and a high recurrence rate. Increasing evidence suggests that human cytomegalovirus (HCMV) infection is related to GBM and leads to GBM cell growth and metastasis. MicroRNAs are important regulators in the growth and metastasis of glioblastoma. This study aimed to demonstrate the role of miR-144-3p in HCMV-positive glioblastoma. We found that, after HCMV infection, the expression of miR-144-3p decreased, whereas the expression of TOP2A increased. Bioinformatics analyses indicated that miR-144-3p directly targets the TOP2A 3'-UTR (Untranslated Region). We discovered that the overexpression of miR-144-3p downregulated the overexpression of TOP2A and inhibited the proliferation, clone formation, and invasion of HCMV-positive glioma in vitro. Taken together, these results show that miR-144-3p inhibited growth and promoted apoptosis in glioma cells by targeting TOP2A.

Lun Y, Huang JC, Long D, et al.
[Molecular Characteristics and Clinical Features of Adults with
Sichuan Da Xue Xue Bao Yi Xue Ban. 2018; 49(4):575-581 [PubMed] Related Publications
OBJECTIVE: To determine the molecular characteristics and clinical features of patients with nucleoporin 98 (NUP98) fusion gene positive acute myeloid leukemia (AML) and the impact of coexistence of
METHODS: Samples of bone marrow or peripheral blood were collected from the adult patients with de novo AML and myelodysplastic syndrome (MDS) in our hospital from July 1st, 2014 to March 1st, 2017.
RESULTS: A total of 197 AML patients participated in this study, including 16 (8.1%) having

Sasanuma H, Tsuda M, Morimoto S, et al.
BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II-DNA complexes.
Proc Natl Acad Sci U S A. 2018; 115(45):E10642-E10651 [PubMed] Free Access to Full Article Related Publications
Women having BRCA1 germ-line mutations develop cancer in breast and ovary, estrogen-regulated tissues, with high penetrance. Binding of estrogens to the estrogen receptor (ER) transiently induces DNA double-strand breaks (DSBs) by topoisomerase II (TOP2) and controls gene transcription. TOP2 resolves catenated DNA by transiently generating DSBs, TOP2-cleavage complexes (TOP2ccs), where TOP2 covalently binds to 5' ends of DSBs. TOP2 frequently fails to complete its catalysis, leading to formation of pathological TOP2ccs. We have previously shown that the endonucleolytic activity of MRE11 plays a key role in removing 5' TOP2 adducts in G

Bai R, Li W, Li Y, et al.
Cytotoxicity of two water-soluble polysaccharides from Codonopsis pilosula Nannf. var. modesta (Nannf.) L.T.Shen against human hepatocellular carcinoma HepG2 cells and its mechanism.
Int J Biol Macromol. 2018; 120(Pt B):1544-1550 [PubMed] Related Publications
Two water-soluble polysaccharides named CPP1a and CPP1c were isolated from C. pilosula Nannf. var. modesta L.T.Shen by hot-water extraction and purified by graded alcohol precipitation and DEAE-52 cellulose column. The structure of CPP1c with higher yield has been characterized while its antitumor activities has not been elucidated. In this study, we firstly analyzed the chemical structure of CPP1a. The results of instrumental analysis combined with chemical analysis showed that CPP1a was composed of →1)- β‑l‑Rhap‑(4→, →1)- β‑Arap‑(5→, →1)- β‑d‑GalpA‑(4→, →1)- β‑d‑Galp‑(6→, terminal‑β‑d‑Glcp in a molar ratio of 1:12:1:10:3 and its relative and absolute molecular weight were 1.01 × 10

Phelps HM, Al-Jadiry MF, Corbitt NM, et al.
Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.
World J Pediatr. 2018; 14(6):585-593 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.
METHODS: Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.
RESULTS: Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).
CONCLUSIONS: These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.

Liu LM, Xiong DD, Lin P, et al.
DNA topoisomerase 1 and 2A function as oncogenes in liver cancer and may be direct targets of nitidine chloride.
Int J Oncol. 2018; 53(5):1897-1912 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The aim of the present study was to determine the role of topoisomerase 1 (TOP1) and topoisomerase 2A (TOP2A) in liver cancer (LC), and to investigate the inhibitory effect of nitidine chloride (NC) on these two topoisomerases. Immunohistochemistry (IHC) staining and microarray or RNA sequencing data mining showed markedly higher expression of TOP1 and TOP2A at the protein and mRNA levels in LC tissues compared with that in control non-tumor tissues. The prognostic values of TOP1 and TOP2A expression were also estimated based on data from The Cancer Genome Atlas. The elevated expression levels of TOP1 and TOP2A were closely associated with poorer overall survival and disease-free survival rates. When patients with LC were divided into high- and low-risk groups according to their prognostic index, TOP1 and TOP2A were highly expressed in the high-risk group. Bioinformatics analyses conducted on the co-expressed genes of TOP1 and TOP2A revealed that the topoisomerases were involved in several key cancer-related pathways, including the 'p53 pathway', 'pathway in cancer' and 'apoptosis signaling pathway'. Reverse transcription-quantitative polymerase chain reaction and IHC performed on triplicate tumor tissue samples from LC xenografts in control or NC-treated nude mice showed that NC treatment markedly reduced the protein and mRNA expression of TOP1 and TOP2A in LC tissues. Molecular docking studies further confirmed the direct binding of NC to TOP1 and TOP2A. In conclusion, the present findings indicate that TOP1 and TOP2A are oncogenes in LC and could serve as potential biomarkers for the prediction of the prognosis of patients with LC and for identification of high-risk cases, thereby optimizing individual treatment management. More importantly, the findings support TOP1 and TOP2A as potential drug targets of NC for the treatment of LC.

Kwinta BM, Wilk A, Trofimiuk-Muldner M, et al.
The relation of pituitary adenomas invasiveness and the proliferative index measured by immunoexpression of topoisomerase IIα.
Endokrynol Pol. 2018; 69(5):530-535 [PubMed] Related Publications
INTRODUCTION: Cavernous sinus invasion by pituitary adenoma affects surgical procedure radicality and consequently the postoperative course and prognosis in pituitary adenoma treatment. The search for pituitary adenoma aggressive behaviour markers is still a matter of debate.
MATERIAL AND METHODS: This study evaluates the relation of pituitary adenoma invasiveness to the expression of topoisomerase IIα in 72 patients who underwent transsphenoidal pituitary surgery. The assessment of tumour growth was conducted according to the Hardy scale as modified by Wilson and the Knosp scale. Topoisomerase IIα expression in tumour specimens was evaluated using immunohistochemical staining.
RESULTS: There was a correlation between the Knosp scale degree and the topoisomerase IIα expression (Spearman R = 0.3611, p < 0.005). The Kruskal-Wallis H test (p = 0.0034) showed that there was a statistically significant topoisomerase IIα expression increase in tumours classified as grade E on the Hardy scale. The topoisomerase IIα expression correlated also with tumour size (Spearman R = 0.4117, p < 0.001). Higher levels of expression were observed in macroadenomas, as compared to microadenomas (p < 0.05, Mann-Whitney test). Topoisomerase IIα expression correlated with cavernous sinus invasion.
CONCLUSIONS: The topoisomerase IIα expression correlated more with invasiveness than with extensiveness, which might make it an eminently useful marker in the assessment of aggressive pituitary adenoma behaviour.

Lv C, Liu X, Zheng Q, et al.
Analysis of topoisomerase I expression and identification of predictive markers for efficacy of topotecan chemotherapy in small cell lung cancer.
Thorac Cancer. 2018; 9(9):1166-1173 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: We evaluated topoisomerase I (TOPO1) expression in patients with small cell lung cancer (SCLC) and identified predictive factors for the efficacy of second-line topotecan chemotherapy.
METHODS: We retrospectively evaluated the records of SCLC patients treated in our department from January 2007 to December 2016 who received second-line topotecan chemotherapy. Patients with archived tumor samples were enrolled. TOPO1 expression levels were evaluated by immunohistochemistry, and the relationships between TOPO1 expression, clinical factors, chemotherapy efficacy, and survival were analyzed.
RESULTS: Of the 78 patients enrolled, 67 showed TOPO1 expression (85.9%). Patients were divided into strong (n = 43) or weak (n = 35) expression groups based on staining intensity. Disease control rates for topotecan were 39.5% and 14.3% in the strong and weak groups, respectively (P = 0.014). Second-line median progression-free survival was 2.2 and 2.0 months (P = 0.057), and median overall survival was 8.1 and 6.0 months (P = 0.199) in the strong and weak positive groups, respectively. Patients were also divided into sensitive (n = 47) and refractory (n = 31) disease groups according to the duration from the onset of first-line therapy to relapse. Median second-line progression-free survival was 2.2 and 1.8 months in the sensitive and refractory relapse groups, respectively (P = 0.005).
CONCLUSIONS: TOPO1 expression was prevalent in SCLC patients. Strong expression was associated with an elevated disease control rate after second-line topotecan chemotherapy. Patients with sensitive disease that relapsed after first-line chemotherapy had better survival than refractory patients who received second-line topotecan chemotherapy.

Meagher NS, Schuster K, Voss A, et al.
Does the primary site really matter? Profiling mucinous ovarian cancers of uncertain primary origin (MO-CUP) to personalise treatment and inform the design of clinical trials.
Gynecol Oncol. 2018; 150(3):527-533 [PubMed] Related Publications
OBJECTIVE: Advanced stage mucinous ovarian cancers are diagnostically and therapeutically challenging. Histotype specific trials have failed due to low recruitment after excluding non-ovarian primaries. Mucinous ovarian cancers are commonly metastatic from other sites however lack definitive diagnostic markers. We suggest a classification of mucinous ovarian cancers of uncertain primary origin 'MO-CUPs' in clinical trials. This study aims to identify drug targets to guide treatment and future trials.
METHODS: We analyzed a large de-identified, multi-platform tumor profiling dataset of MO-CUPs enriched for advanced stage and recurrent cases submitted to Caris Life Sciences. Available data included a 45-gene next-generation sequencing (NGS) panel, gene amplification of HER2 and cMET and 18 immunohistochemical (IHC) markers of drug sensitivity/resistance.
RESULTS: Mucinous tumors from 333 patients were analyzed, including 38 borderline tumors and 295 invasive cancers. The most common mutations in a subset (n = 128) of invasive cancers were KRAS (60%), TP53 (38%), PIK3CA (13%) and PTEN (9%). Borderline tumors had higher rates of BRAF mutations, and PGP and TOP2A overexpression than invasive cases. KRAS mutant invasive cancers had lower expression of thymidylate synthase (p = 0.01) and higher expression of TUBB3 (p = 0.01) than KRAS wildtype tumors.
CONCLUSIONS: To our knowledge, this is the largest series profiling mucinous ovarian cancers and almost certainly includes cases of ovarian and non-ovarian origin. Given the difficulty recruiting patients to histotype-specific trials in rare subsets of ovarian cancer, it may be more important to focus on identifying potential treatment targets and to personalise treatment and design clinical trials in MO-CUPS agnostic of primary site to overcome these issues.

Zimmermann M, Murina O, Reijns MAM, et al.
CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions.
Nature. 2018; 559(7713):285-289 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The observation that BRCA1- and BRCA2-deficient cells are sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP) has spurred the development of cancer therapies that use these inhibitors to target deficiencies in homologous recombination

Hashimoto Y, Penas-Prado M, Zhou S, et al.
Rethinking medulloblastoma from a targeted therapeutics perspective.
J Neurooncol. 2018; 139(3):713-720 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
INTRODUCTION: Medulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge. Analysis of therapeutic targets can provide opportunities for the selection of agents.
METHODS: Using multiplatform analysis, 36 medulloblastomas were extensively profiled from 2009 to 2015. Immunohistochemistry, next generation sequencing, chromogenic in situ hybridization, and fluorescence in situ hybridization were used to identify overexpressed proteins, immune checkpoint expression, mutations, tumor mutational load, and gene amplifications.
RESULTS: High expression of MRP1 (89%, 8/9 tumors), TUBB3 (86%, 18/21 tumors), PTEN (85%, 28/33 tumors), TOP2A (84%, 26/31 tumors), thymidylate synthase (TS; 80%, 24/30 tumors), RRM1 (71%, 15/21 tumors), and TOP1 (63%, 19/30 tumors) were found in medulloblastoma. TOP1 was found to be enriched in metastatic tumors (90%; 9/10) relative to posterior fossa cases (50%; 10/20) (p = 0.0485, Fisher exact test), and there was a positive correlation between TOP2A and TOP1 expression (p = 0.0472). PD-1 + T cell tumor infiltration was rare, PD-L1 tumor expression was uncommon, and TML was low, indicating that immune checkpoint inhibitors as a monotherapy should not necessarily be prioritized for therapeutic consideration based on biomarker expression. Gene amplifications such as those of Her2 or EGFR were not found. Several unique mutations were identified, but their rarity indicates large-scale screening efforts would be necessary to identify sufficient patients for clinical trial inclusion.
CONCLUSIONS: Therapeutics are available for several of the frequently expressed targets, providing a justification for their consideration in the setting of medulloblastoma.

Wen P, Chidanguro T, Shi Z, et al.
Identification of candidate biomarkers and pathways associated with SCLC by bioinformatics analysis.
Mol Med Rep. 2018; 18(2):1538-1550 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Small cell lung cancer (SCLC) is one of the highly malignant tumors and a serious threat to human health. The aim of the present study was to explore the underlying molecular mechanisms of SCLC. mRNA microarray datasets GSE6044 and GSE11969 were downloaded from Gene Expression Omnibus database, and the differentially expressed genes (DEGs) between normal lung and SCLC samples were screened using GEO2R tool. Functional and pathway enrichment analyses were performed for common DEGs using the DAVID database, and the protein‑protein interaction (PPI) network of common DEGs was constructed by the STRING database and visualized with Cytoscape software. In addition, the hub genes in the network and module analysis of the PPI network were performed using CentiScaPe and plugin Molecular Complex Detection. Finally, the mRNA expression levels of hub genes were validated in the Oncomine database. A total of 150 common DEGs with absolute fold‑change >0.5, including 66 significantly downregulated DEGs and 84 upregulated DEGs were obtained. The Gene Ontology term enrichment analysis suggested that common upregulated DEGs were primarily enriched in biological processes (BPs), including 'cell cycle', 'cell cycle phase', 'M phase', 'cell cycle process' and 'DNA metabolic process'. The common downregulated genes were significantly enriched in BPs, including 'response to wounding', 'positive regulation of immune system process', 'immune response', 'acute inflammatory response' and 'inflammatory response'. Kyoto Encyclopedia of Genes and Genomes pathway analysis identified that the common downregulated DEGs were primarily enriched in the 'complement and coagulation cascades' signaling pathway; the common upregulated DEGs were mainly enriched in 'cell cycle', 'DNA replication', 'oocyte meiosis' and the 'mismatch repair' signaling pathways. From the PPI network, the top 10 hub genes in SCLC were selected, including topoisomerase IIα, proliferating cell nuclear antigen, replication factor C subunit 4, checkpoint kinase 1, thymidylate synthase, minichromosome maintenance protein (MCM) 2, cell division cycle (CDC) 20, cyclin dependent kinase inhibitor 3, MCM3 and CDC6, the mRNA levels of which are upregulated in Oncomine SCLC datasets with the exception of MCM2. Furthermore, the genes in the significant module were enriched in 'cell cycle', 'DNA replication' and 'oocyte meiosis' signaling pathways. Therefore, the present study can shed new light on the understanding of molecular mechanisms of SCLC and may provide molecular targets and diagnostic biomarkers for the treatment and early diagnosis of SCLC.

Gao HY, Wang W, Luo XG, et al.
Screening of prognostic risk microRNAs for acute myeloid leukemia.
Hematology. 2018; 23(10):747-755 [PubMed] Related Publications
Objectives This study aimed to investigate the risk miRNAs (microRNAs) for AML (acute myeloid leukemia) prognosis and related regulatory mechanisms. Methods MiRNA and gene expression data, as well as clinical data of 176 patients were first downloaded from TCGA. Then miRNAs and genes significantly affecting the survival time based on KM survival curve were identified using Log Rank test. Next, COX proportional-hazard regression analysis was performed to screen the risk miRNAs (P-value < 0.05). Common genes from survival analysis and predicted by miRWalk were used to construct the miRNA regulatory network with the risk miRNAs. Finally, a protein-protein interaction (PPI) network was constructed, as well as functional annotation and pathway enrichment analysis. Results The survival analysis revealed 33 miRNAs and 1,377 genes significantly affecting the survival time. HR values of nine miRNAs (up-regulated hsa-mir-606, 520a, 137, 362, 599, 600, 202, 639and down-regulated 502) were either >1 or <1. The miRNA regulatory network contained 477 nodes and 944 edges. The top ten genes of the constructed PPI network were EGFR, EIF4G1, REL, TOP1, COL14A1, HDAC3, MRPL49, PSMA2, TOP2A and VCAM1 successively. According to pathway enrichment analysis, 6 KEGG pathways and 6 REACTOME pathways were obtained respectively. Conclusion Up-regulated hsa-mir-520a, 599, 606, 137 and 362 may increase the prognostic risk for AML patients via regulating the expression of corresponding target genes, especially COL14A1, HDAC3, REL, EGFR, PSMA2, EIF4G1, MRPL49 and TOP1.

Hsu JM, Xia W, Hsu YH, et al.
STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion.
Nat Commun. 2018; 9(1):1908 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying PD-L1 enrichment in CSCs remain unclear. Here, we demonstrate that epithelial-mesenchymal transition (EMT) enriches PD-L1 in CSCs by the EMT/β-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1. The axis is also utilized by the general cancer cell population, but it has much more profound effect on CSCs as EMT induces more STT3 in CSCs than in non-CSCs. We further identify a non-canonical mesenchymal-epithelial transition (MET) activity of etoposide, which suppresses the EMT/β-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear β-catenin reduction, leading to PD-L1 downregulation of CSCs and non-CSCs and sensitization of cancer cells to anti-Tim-3 therapy. Together, our results link MET to PD-L1 stabilization through glycosylation regulation and reveal it as a potential strategy to enhance cancer immunotherapy efficacy.

Litviakov N, Tsyganov M, Larionova I, et al.
Expression of M2 macrophage markers YKL-39 and CCL18 in breast cancer is associated with the effect of neoadjuvant chemotherapy.
Cancer Chemother Pharmacol. 2018; 82(1):99-109 [PubMed] Related Publications
PURPOSE: High activity of enzyme TOP2a in tumor cells is known to be associated with sensitivity to anthracycline chemotherapy, but 20% of such patients do not show clinical response. Tumor microenvironment, including tumor-associated macrophages (TAM), is an essential factor defining the efficiency of chemotherapy. In the present study, we analyzed the expression of M2 macrophage markers, YKL-39 and CCL18, in tumors of breast cancer patients received anthracycline-based NAC.
METHODS: Patients were divided into two groups according to the level of doxorubicin sensitivity marker TOP2a: DOX-Sense and DOX-Res groups. Expression levels of TOR2a, CD68, YKL-39 and CCL18 genes were analyzed by qPCR, the amplification of TOR2a gene locus was assessed by the microarray assay. Clinical and pathological responses to neoadjuvant chemotherapy were assessed.
RESULTS: We found that the average level of TOP2a expression in patients of DOX-Sense group was almost 10 times higher than in patients of DOX-Res group, and the expression of CD68 was 3 times higher in the DOX-Sense group compared to DOX-Res group. We demonstrated that expression levels of M2-derived cytokines but not the amount of TAM is indicative for clinical and pathological chemotherapy efficacy in breast cancer patients. Out of 8 patients from DOX-Sense group who did not respond to neoadjuvant chemotherapy (NAC), 7 patients had M2+ macrophage phenotype (YKL-39
CONCLUSIONS: Thus, we showed that in patients with breast cancer who received anthracycline-containing NAC the absence of clinical response is associated with the presence of M2+ macrophage phenotype (YKL-39-CCL18 + or YKL-39 + CCL18-) based on TOP2a overexpression data.

An X, Xu F, Luo R, et al.
The prognostic significance of topoisomerase II alpha protein in early stage luminal breast cancer.
BMC Cancer. 2018; 18(1):331 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Topoisomerase II alpha (TOP2A) protein has been shown to be a proliferation marker associated with tumor grade and Ki67 index. The prognostic effect of TOP2A seems different among different subtypes of breast cancer. The current study evaluated the prognostic impact of TOP2A protein on luminal breast cancer.
METHOD: Altogether 434 stage I-II luminal breast cancer patients who underwent curative surgery in Sun Yat-Sen University Cancer Center between 2007 and 2009 were enrolled. TOP2A protein expression was assessed by immunohistochemistry. Clinical and pathological data were retrospectively collected.
RESULT: With a cut-off value of 30%, 127 (29.3%) patients were classified as TOP2A overexpression. TOP2A overexpression was associated with a higher tumor grade and Ki67 index. Patients with TOP2A high expression showed a significantly higher rate of distant metastasis and shorter distant metastasis free survival (DMFS) compared with patients with low TOP2A expression. The prognostic influence of TOP2A expression was more significant in years 5-8 after diagnosis, and more pronounced in stage II patients, luminal B disease, and patients treated with adjuvant endocrine therapy alone. Multivariate survival analysis revealed TOP2A overexpression was an independent fact for worse DMFS.
CONCLUSION: TOP2A protein showed a time dependent influence on prognosis in stage I-II luminal breast cancer, suggesting it might be a potential predictor of late recurrence for this group of patients.

Wang TL, Song YQ, Ren YW, et al.
Dual-specificity phosphatase 6 genetic variants associated with risk of lung squamous cell carcinoma in Han Chinese.
J Cancer Res Ther. 2018; 14(Supplement):S72-S78 [PubMed] Related Publications
Background: Nonsmall cell lung cancer (NSCLC) mainly contains adenocarcinoma (AC) and squamous cell carcinoma (SqCC). This study investigated single nucleotide polymorphism (SNP) of topoisomerase II alpha (TOP2A) and dual-specificity phosphatase 6 (DUSP6) in a hospital-based case and control cohort of individuals for association with risk of different histological subtypes of NSCLC.
Materials and Methods: A total of 454 (237 SqCC and 217 AC) NSCLC patients, and 454 healthy controls were recruited for analysis of TOP2A rs471692 and DUSP6 rs2279574 genotypes using the TaqMan polymerase chain reaction technique.
Results: TOP2A rs471692 and DUSP6 rs2279574 SNPs were in complete linkage disequilibrium; however, frequency of DUSP6 rs2279574 genotype was significantly different between the case and control, that is, DUSP6 rs2279574a/A and A/C genotypes might contribute to an increased risk of lung squamous carcinoma compared with the C/C genotype. Moreover, DUSP6 rs2279574 AA genotype was also significantly associated with advanced stages of lung cancer. In contrast, frequency of the TOP2A rs471692 genotype had no association between cases and controls (P = 0.906). Genotype frequency of DUSP6 rs2279574 was 11.9% for C/C, 43.6% for C/A, and 44.5% for A/A in the case versus 16.7% C/C, 43.4% C/A, and 39.9% A/A in the control population (χ
Conclusion: Individuals are carrying DUSP6 rs2279574 AA and AC genotypes associated with an increased risk in developing lung squamous carcinoma in Han Chinese and with advanced NSCLC stages.

Kjeldsen E, Nielsen CJF, Roy A, et al.
Characterization of Camptothecin-induced Genomic Changes in the Camptothecin-resistant T-ALL-derived Cell Line CPT-K5.
Cancer Genomics Proteomics. 2018 Mar-Apr; 15(2):91-114 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Acquisition of resistance to topoisomerase I (TOP1)-targeting camptothecin (CPT) derivatives is a major clinical problem. Little is known about the underlying chromosomal and genomic mechanisms. We characterized the CPT-K5 cell line expressing mutant CPT-resistant TOP1 and its parental T-cell derived acute lymphoblastic leukemia CPT-sensitive RPMI-8402 cell line by karyotyping and molecular genetic methods, including subtractive oligo-based array comparative genomic hybridization (soaCGH) analysis. Karyotyping revealed that CPT-K5 cells had acquired additional structural aberrations and a reduced modal chromosomal number compared to RPMI-8402. soaCGH analysis identified vast copy number alterations and >200 unbalanced DNA breakpoints distributed unevenly across the chromosomal complement in CPT-K5. In addition, the short tandem repeat alleles were found to be highly different between CPT-K5 and its parental cell line. We identified copy number alterations affecting genes important for maintaining genome integrity and reducing CPT-induced DNA damage. We show for the first time that short tandem repeats are targets for TOP1 cleavage, that can be differentially stimulated by CPT.

Infante Lara L, Fenner S, Ratcliffe S, et al.
Coupling the core of the anticancer drug etoposide to an oligonucleotide induces topoisomerase II-mediated cleavage at specific DNA sequences.
Nucleic Acids Res. 2018; 46(5):2218-2233 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Etoposide and other topoisomerase II-targeted drugs are important anticancer therapeutics. Unfortunately, the safe usage of these agents is limited by their indiscriminate induction of topoisomerase II-mediated DNA cleavage throughout the genome and by a lack of specificity toward cancer cells. Therefore, as a first step toward constraining the distribution of etoposide-induced DNA cleavage sites and developing sequence-specific topoisomerase II-targeted anticancer agents, we covalently coupled the core of etoposide to oligonucleotides centered on a topoisomerase II cleavage site in the PML gene. The initial sequence used for this 'oligonucleotide-linked topoisomerase inhibitor' (OTI) was identified as part of the translocation breakpoint of a patient with acute promyelocytic leukemia (APL). Subsequent OTI sequences were derived from the observed APL breakpoint between PML and RARA. Results indicate that OTIs can be used to direct the sites of etoposide-induced DNA cleavage mediated by topoisomerase IIα and topoisomerase IIβ. OTIs increased levels of enzyme-mediated cleavage by inhibiting DNA ligation, and cleavage complexes induced by OTIs were as stable as those induced by free etoposide. Finally, OTIs directed against the PML-RARA breakpoint displayed cleavage specificity for oligonucleotides with the translocation sequence over those with sequences matching either parental gene. These studies demonstrate the feasibility of using oligonucleotides to direct topoisomerase II-mediated DNA cleavage to specific sites in the genome.

Delgado JL, Hsieh CM, Chan NL, Hiasa H
Topoisomerases as anticancer targets.
Biochem J. 2018; 475(2):373-398 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However, traditional or nonspecific anticancer drugs are still important for the treatment of many cancer patients whose cancers either do not respond to or have developed resistance to cancer-specific anticancer agents. DNA topoisomerases, especially type IIA topoisomerases, are proved therapeutic targets of anticancer and antibacterial drugs. Clinically successful topoisomerase-targeting anticancer drugs act through topoisomerase poisoning, which leads to replication fork arrest and double-strand break formation. Unfortunately, this unique mode of action is associated with the development of secondary cancers and cardiotoxicity. Structures of topoisomerase-drug-DNA ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. Recent advances in the field have suggested a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs. It may also be possible to design catalytic inhibitors of topoisomerases by targeting certain inactive conformations of these enzymes. Furthermore, identification of various new bacterial topoisomerase inhibitors and regulatory proteins may inspire the discovery of novel human topoisomerase inhibitors. Thus, topoisomerases remain as important therapeutic targets of anticancer agents.

Ganguli A, Ornob A, Spegazzini N, et al.
Pixelated spatial gene expression analysis from tissue.
Nat Commun. 2018; 9(1):202 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Here, we present a technique that performs on-chip picoliter real-time reverse transcriptase loop mediated isothermal amplification (RT-LAMP) reactions on a histological tissue section without any analyte purification while preserving the native spatial location of the nucleic acid molecules. We demonstrate this method by amplifying TOP2A messenger RNA (mRNA) in a prostate cancer xenograft with 100 µm spatial resolution and by visualizing the variation in threshold time of amplification across the tissue. The on-chip reaction was validated by mRNA fluorescence in situ hybridization (mFISH) from cells in the tissue section. The entire process, from tissue loading on microchip to results from RT-LAMP can be carried out in less than 2 h. We anticipate that this technique, with its ease of use, fast turnaround, and quantitative molecular outputs, would become an invaluable tissue analysis tool for researchers and clinicians in the biomedical arena.

Nuncia-Cantarero M, Martinez-Canales S, Andrés-Pretel F, et al.
Functional transcriptomic annotation and protein-protein interaction network analysis identify NEK2, BIRC5, and TOP2A as potential targets in obese patients with luminal A breast cancer.
Breast Cancer Res Treat. 2018; 168(3):613-623 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
PURPOSE: Although obesity is a risk factor for breast cancer, little effort has been made in the identification of druggable molecular alterations in obese-breast cancer patients. Tumors are controlled by their surrounding microenvironment, in which the adipose tissue is a main component. In this work, we intended to describe molecular alterations at a transcriptomic and protein-protein interaction (PPI) level between obese and non-obese patients.
METHODS AND RESULTS: Gene expression data of 269 primary breast tumors were compared between normal-weight (BMI < 25, n = 130) and obese (IMC > 30, n = 139) patients. No significant differences were found for the global breast cancer population. However, within the luminal A subtype, upregulation of 81 genes was observed in the obese group (FC ≥ 1.4). Next, we explored the association of these genes with patient outcome, observing that 39 were linked with detrimental outcome. Their PPI map formed highly compact cluster and functional annotation analyses showed that cell cycle, cell proliferation, cell differentiation, and cellular response to extracellular stimuli were the more altered functions. Combined analyses of genes within the described functions are correlated with poor outcome. PPI network analyses for each function were to search for druggable opportunities. We identified 16 potentially druggable candidates. Among them, NEK2, BIRC5, and TOP2A were also found to be amplified in breast cancer, suggesting that they could act as strategic players in the obese-deregulated transcriptome.
CONCLUSION: In summary, our in silico analysis describes molecular alterations of luminal A tumors and proposes a druggable PPI network in obese patients with potential for translation to the clinical practice.

Neama RAA, Habib MA, Ali SA, et al.
Assessment of topoisomerase II-alpha gene status by dual color chromogenic
Indian J Pathol Microbiol. 2017 Oct-Dec; 60(4):475-480 [PubMed] Related Publications
BACKGROUND: The human epidermal growth factor receptor 2(HER2) proto-oncogene is overexpressed or amplified in approximately 15%-25% of invasive breast cancers. Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. Hence, the determination of genetic alteration (amplification or deletion) of both genes is considered as an important predictive factor that determines the response of breast cancer patients to treatment. The aims of this study are to determinate TOP2A status gene amplification in a set of Iraqi patients with breast cancer that have had an equivocal (2+) and positive HER2/neu by immunohistochemistry (IHC) and to compare the results with estrogen receptor (ER) and progesterone receptor (PR) and HER2/neu status.
PATIENTS AND METHODS: A cross-sectional prospective study done on 53 patients with invasive breast carcinoma. Twenty-six out of total 53 cases were positive HER2/neu (3+), the remaining 27 equivocal HER2-IHC (2+) cases reanalyzed using dual-color chromogenic in situ hybridization (ZytoVision) probe kit for further identification of HER2/neu gene amplification. Using chromogenic in situ hybridization (CISH), TOP2A gene status determination was done for all cases.
RESULTS: There is a direct significant correlation between TOP2A gene amplification and HER2/neu positivity, P < 0.05 in that 15 (39.4%) out of 38 positive HER2/neu cases were associated with topoisomerase gene amplification. Regarding relation of topoisomerase gene to hormone receptor status (ER and PR), there was a significant negative relationship between the gene and ER receptor status. The higher level of gene amplification was noticed in ER and PR negative cases in about 13 (43.3%) and 14 (48.2%) for ER and PR, respectively.
CONCLUSION: TOP2A gene status has a significantly positive correlation with HER2/neu status while it has a significantly negative correlation with hormone receptor status.

McKenzie JA, Mbofung RM, Malu S, et al.
The Effect of Topoisomerase I Inhibitors on the Efficacy of T-Cell-Based Cancer Immunotherapy.
J Natl Cancer Inst. 2018; 110(7):777-786 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Background: Immunotherapy has increasingly become a staple in cancer treatment. However, substantial limitations in the durability of response highlight the need for more rational therapeutic combinations. The aim of this study is to investigate how to make tumor cells more sensitive to T-cell-based cancer immunotherapy.
Methods: Two pairs of melanoma patient-derived tumor cell lines and their autologous tumor-infiltrating lymphocytes were utilized in a high-throughput screen of 850 compounds to identify bioactive agents that could be used in combinatorial strategies to improve T-cell-mediated killing of tumor cells. RNAi, overexpression, and gene expression analyses were utilized to identify the mechanism underlying the effect of Topoisomerase I (Top1) inhibitors on T-cell-mediated killing. Using a syngeneic mouse model (n = 5 per group), the antitumor efficacy of the combination of a clinically relevant Top1 inhibitor, liposomal irinotecan (MM-398), with immune checkpoint inhibitors was also assessed. All statistical tests were two-sided.
Results: We found that Top1 inhibitors increased the sensitivity of patient-derived melanoma cell lines (n = 7) to T-cell-mediated cytotoxicity (P < .001, Dunnett's test). This enhancement is mediated by TP53INP1, whose overexpression increased the susceptibility of melanoma cell lines to T-cell cytotoxicity (2549 cell line: P = .009, unpaired t test), whereas its knockdown impeded T-cell killing of Top1 inhibitor-treated melanoma cells (2549 cell line: P < .001, unpaired t test). In vivo, greater tumor control was achieved with MM-398 in combination with α-PD-L1 or α-PD1 (P < .001, Tukey's test). Prolonged survival was also observed in tumor-bearing mice treated with MM-398 in combination with α-PD-L1 (P = .002, log-rank test) or α-PD1 (P = .008, log-rank test).
Conclusions: We demonstrated that Top1 inhibitors can improve the antitumor efficacy of cancer immunotherapy, thus providing the basis for developing novel strategies using Top1 inhibitors to augment the efficacy of immunotherapy.

Shaojun C, Li H, Haixin H, Guisheng L
Expression of Topoisomerase 1 and carboxylesterase 2 correlates with irinotecan treatment response in metastatic colorectal cancer.
Cancer Biol Ther. 2018; 19(3):153-159 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Topoisomerase 1 (TOPO-1) and carboxylesterase 2 (CES-2) are found to play crucial roles in the pathogenesis of various cancers. The prognostic role of TOPO-1 and CES-2 in patients with metastatic colorectal cancer (mCRC) who underwent irinotecan chemotherapy was largely unknown. In the current study, we assessed the expression of TOPO-1 and CES-2 in mCRC and analyzed its potential relevance to irinotecan based therapy. A total of 98 patients with mCRC were included in this study. The expression of TOPO-1 and CES-2 in mCRC tissues was evaluated by immunohistochemistry. For TOPO-1, 46 patients showed high expression and 52 patients showed low expression. For CES-2, 53 patients showed high expression and 45 patients showed low expression. The correlation between TOPO-1 or CES-2 expression and clinicopathological characteristics of mCRC patients was analyzed. Neither TOPO-1 nor CES-2 had significant correlation with age, gender, tumor site, tumor grade and metastatic sites in mCRC patients. However, high expression of CES-2 but not TOP-1 was positively correlated with better curative effect. Kaplan-Meier and log-rank test were applied to assess the correlation between progression-free survival (PFS)/overall survival (OS) and TOPO-1 or CES-2 expression in mCRC patients. High expression of TOPO-1 and CES-2 are correlated with longer PFS and OS. In summary, our findings suggest that TOPO-1 and CES-2 may play important roles irinotecan sensitivity in mCRC patients. Evaluation of expression of TOPO-1 and CES-2 may provide preliminary clinical evidence for the management of irinotecan-based therapy in mCRC patients.

Kawale AS, Povirk LF
Tyrosyl-DNA phosphodiesterases: rescuing the genome from the risks of relaxation.
Nucleic Acids Res. 2018; 46(2):520-537 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Tyrosyl-DNA Phosphodiesterases 1 (TDP1) and 2 (TDP2) are eukaryotic enzymes that clean-up after aberrant topoisomerase activity. While TDP1 hydrolyzes phosphotyrosyl peptides emanating from trapped topoisomerase I (Top I) from the 3' DNA ends, topoisomerase 2 (Top II)-induced 5'-phosphotyrosyl residues are processed by TDP2. Even though the canonical functions of TDP1 and TDP2 are complementary, they exhibit little structural or sequence similarity. Homozygous mutations in genes encoding these enzymes lead to the development of severe neurodegenerative conditions due to the accumulation of transcription-dependent topoisomerase cleavage complexes underscoring the biological significance of these enzymes in the repair of topoisomerase-DNA lesions in the nervous system. TDP1 can promiscuously process several blocked 3' ends generated by DNA damaging agents and nucleoside analogs in addition to hydrolyzing 3'-phosphotyrosyl residues. In addition, deficiency of these enzymes causes hypersensitivity to anti-tumor topoisomerase poisons. Thus, TDP1 and TDP2 are promising therapeutic targets and their inhibitors are expected to significantly synergize the effects of current anti-tumor therapies including topoisomerase poisons and other DNA damaging agents. This review covers the structural aspects, biology and regulation of these enzymes, along with ongoing developments in the process of discovering safe and effective TDP inhibitors.

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