ArticleMolecular oncology2015
Topoisomerase-1 and -2A gene copy numbers are elevated in mismatch repair-proficient colorectal cancers.
Article in Molecular oncology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 25 citations in OpenAlex.
- A phase II study of Epirubicin in oxaliplatin-resistant patients with metastatic colorectal cancer and TOP2A gene amplification.BMC cancer · 2016Trial
- Integrated bioinformatics and experimental validation reveal that CENPF activates mTORC1 signaling to promote colorectal cancer progression.Cancer cell international · 2026Article
- Circular RNA Ubiquitin-associated Protein 2 Silencing Suppresses Bladder Cancer Progression by Downregulating DNA Topoisomerase 2-alpha Through Sponging miR-496.European urology open science · 2023Article
- Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling.Cells · 2023Article
- An integrated multi-omics analysis of topoisomerase family in pan-cancer: Friend or foe?PloS one · 2022Article
- Article
- Identification of Hub Genes in Different Stages of Colorectal Cancer through an Integrated Bioinformatics Approach.International journal of environmental research and public health · 2021Article
- Role of Stress-Survival Pathways and Transcriptomic Alterations in Progression of Colorectal Cancer: A Health Disparities Perspective.International journal of environmental research and public health · 2021Review
- Long Non-Coding RNA: A Potential Strategy for the Diagnosis and Treatment of Colorectal Cancer.Frontiers in oncology · 2021Review
- Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression.Nature communications · 2020Article
- An Explorative Analysis ofCancers · 2020Article
- Identification of Core Gene Expression Signature and Key Pathways in Colorectal Cancer.Frontiers in genetics · 2020Article
- Exploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models.BMC bioinformatics · 2019Article
- Screening key lncRNAs for human rectal adenocarcinoma based on lncRNA-mRNA functional synergistic network.Cancer medicine · 2019Article
- Identification of Common Genes Refers to Colorectal Carcinogenesis with Paired Cancer and Noncancer Samples.Disease markers · 2018Article
- Epigenomic Regulation of Androgen Receptor Signaling: Potential Role in Prostate Cancer Therapy.Cancers · 2017Review
- High microsatellite instability (MSI-H) colorectal carcinoma: a brief review of predictive biomarkers in the era of personalized medicine.Familial cancer · 2016Review
- Article
- Topoisomerase-1 and -2A gene copy numbers are elevated in mismatch repair-proficient colorectal cancers.Molecular oncology · 2015Article
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionTopoisomerase 1 (TOP1) and 2A (TOP2A) are potential predictive biomarkers for irinotecan and anthracycline treatment, respectively, in colorectal cancer (CRC), and we have recently reported a high frequency of gene gain of the TOP1 and TOP2A genes in CRC. Furthermore, Mismatch Repair (MMR) subtypes of CRC have been associated with benefit from adjuvant chemotherapy of primary CRC. Given the involvement of the topoisomerase enzymes in DNA replication and repair, we raised the hypothesis that an association may exist between TOP gene copy numbers and MMR proficiency/deficiency in CRC. MATERIAL AND
methodsTest cohort: FISH analysis with an in-house TOP1/CEN20 probe mix and a commercially available TOP2A/CEN17 (Dako, Glostrup, Denmark) probe mix was performed on archival formalin fixed paraffin embedded (FFPE) tissue samples from 18 patients with proficient MMR (pMMR) CRC and 18 patients with deficient MMR (dMMR) CRC. TOP1 and TOP2A gene copy numbers and their ratios per nucleus were correlated with MMR status using the Mann-Whitney test. Validation cohort: FFPE samples from 154 patients with primary stage III CRC (originally included in the RANX05 study) were classified according to MMR status by immunohistochemical analysis using validated antibodies for MLH1, MLH2, MSH6 and PMS2, and information on TOP1, CEN20, TOP2A and CEN17 status was previously published for this cohort.
resultsThe observed TOP1 gene copy numbers in the 36 CRC test cohort were significantly greater (p < 0.01) in the pMMR subgroup (mean: 3.84, SD: 2.03) than in the dMMR subgroup (mean: 1.50, SD: 0.12). Similarly, the TOP2A copy numbers were significantly greater (p < 0.01) in the pMMR subgroup (mean: 1.99, SD: 0.52) than in the dMMR subgroup (mean: 1.52, SD: 0.10). These findings were confirmed in the validation cohort, where in the pMMR subgroup 51% had ≥2 extra TOP1 copies per cell, while all tumors classified as dMMR had diploid TOP1 status and mean TOP2A copy numbers were 2.30 (SD: 1.36) and 1.80 (SD: 0.31) (p = 0.01) in the pMMR subgroup vs. dMMR subgroup, respectively. DISCUSSION AND
conclusionOur results show that TOP1 and TOP2A gene copy numbers are increased in the pMMR subgroup. We propose that this preference may reflect a selective pressure to gain and/or maintain the gained extra copies of topoisomerase genes whose products are required to cope with high replication stress present in the pMMR tumors, thereby providing a survival advantage selectively in pMMR tumors. Future studies should test this concept and explore potential differences between pMMR and dMMR tumors in response to Top1 and Top2 inhibitors.
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