An integrated multi-omics analysis of topoisomerase family in pan-cancer: Friend or foe?

Abstract

Background Topoisomerases are nuclear enzymes that get to the bottom of topological troubles related with DNA all through a range of genetic procedures. More and more studies have shown that topoisomerase-mediated DNA cleavage plays crucial roles in tumor cell death and carcinogenesis. There is however still a lack of comprehensive multi-omics studies related to topoisomerase family genes from a pan-cancer perspective. Methods In this study, a multiomics pan-cancer analysis of topoisomerase family genes was conducted by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from The Cancer Genome Atlas (TCGA), 481 small molecule drug response data from cancer therapeutics response portal (CTRP) as well as normal tissue data from Genotype-Tissue Expression (GTEx). Finally, overall activity-level analyses of topoisomerase in pan-cancers were performed by gene set variation analysis (GSVA), together with differential expression, clinical relevancy, immune cell infiltration and regulation of cancer-related pathways. Results Dysregulated gene expression of topoisomerase family were related to genomic changes and abnormal epigenetic modifications. The expression levels of topoisomerase family genes could significantly impact cancer progression, intratumoral heterogeneity, alterations in the immunological condition and regulation of the cancer marker-related pathways, which in turn caused the differences in potential drugs sensitivity and the distinct prognosis of patients. Conclusion It was anticipated that topoisomerase family genes would become novel prognostic biomarkers for cancer patients and provide new insights for the diagnosis and treatment of tumors.

Exploration of potential molecular mechanisms and genotoxicity of anti-cancer drugs using next generation knowledge discovery methods

“…Topoisomerase expression has been found to be increased in a variety of solid tumors and the inhibition of topoisomerases is one of the key strategies in the development of anti-cancer therapy. 15 Etoposide is a semisynthetic product of podophyllotoxin, which is obtained from Podophyllum peltatum, also known as mandrake root. 16 , 17…”

“…Topoisomerase expression has been found to be increased in a variety of solid tumors and the inhibition of topoisomerases is one of the key strategies in the development of anti-cancer therapy. 15 Etoposide is a semisynthetic product of podophyllotoxin, which is obtained from Podophyllum peltatum, also known as mandrake root. 16,17 It binds to topoisomerase II and inhibits its activity, resulting in breaks in either single or double strands of DNA, as well as obstruction of DNA replication and transcription, leading to apoptotic cell death.…”

Evaluation of the Anticancer and Biological Activities of Istaroxime via Ex Vivo Analyses, Molecular Docking and Conceptual Density Functional Theory Computations

“…The FDA-approved CPT derivatives topotecan and irinotecan have demonstrated the potential for use of topoisomerase I inhibitors and have led to the importance of targeting topoisomerase I in the treatment of cancers that rely on the function of topoisomerase I for survival, such as highly malignant tumor cells [44][45][46][47].…”

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

“…Cytosine methylation impacts tumorigenicity, as 5methylcytosine is mutagenic and can undergo spontaneous hydrolytic deamination, resulting in C → T transitions [94][95][96][97]. Clinical and integrated multi-omics analyses suggested the relevance of topoisomerases in tumor heterogeneity [98,99].…”