Title: Pan-cancer multi-omics analyses reveal TOP2A as an oncogene causing poor prognosis in multiple tumors

Abstract

Background: The topoisomerase II alpha (TOP2A) gene, which is located on chromosome 17 in humans, is an important nuclear protein that controls the topological state of DNA during DNA replication and transcription. A growing body of evidence indicates that TOP2A play a critical role in cancer progression and metastasis formation. However, no studies have conducted systematic analysis of TOP2A from a pan-cancer perspective. Method: Based on the multi-omics data of pan-cancer in the TCGA database, we explored the value of TOP2A in pan-cancer using various bioinformatics algorithms. Result: The expression of TOP2A was upregulated in almost all types of cancer. High expression of TOP2A was associated with intratumoral subtype heterogeneity, metastasis, cancer progression and poor prognosis in multiple cancer types. In addition, extensive genomic alterations and abnormal epigenetic modification pattern mediated the dysregulation of TOP2A expression in tumors. More importantly, high expression of TOP2A showed significant positive correlation with multiple cancer markers, including RNAss, LOH, MATH, TMB, MSI, HRD, neoantigen, tumor ploidy. In tumor microenvironment analysis, we found that the high expression of TOP2A can increase the tumor purity and mediate immunosuppression via the recruitment of Th2 cell and MDSC in almost all tumors. Compared with some famous markers, TOP2A was also able to predict the response to immunotherapy accurately in a wide variety of cancer types. In anticancer drug screening, etoposide, TPCA 1 and vorinostat were identified as potential effective drugs for targeting TOP2A. Pathway enrichment analysis showed that TOP2A can activate apoptosis, cell-cycle and EMT in almost all tumors. Finally, experiments performed in vitro demonstrated that knockout of TOP2A can inhibite hepatocellular carcinoma cell proliferation, colony formation, migration and cell-cycle. Conclusion: Our study revealed that TOP2A may serve as an oncogene and play tumor promoting roles from a multi-omic perspective. High expression of TOP2A might be a potential diagnostic and prognostic marker. Therefore, we proposed that targeting TOP2A may help might contribute to change immunosuppressive microenvironments and improve the long-term prognosis of cancer patients.