DNA Topoisomerase II Mutations in Cancer: Structural Impact and Drug Response in High-grade Serous Ovarian Carcinoma

Topoisomerases are essential enzymes that resolve DNA topological stress during replication and transcription. In mammalian cells, the two isoforms, TOP2A and TOP2B, differ in expression profiles and functions. TOP2A is a key regulator of cell division, mainly expressed in rapidly dividing cells, such as cancer cells, and is therefore the primary target of several chemotherapeutic molecules. In contrast, TOP2B is ubiquitously expressed in both dividing and non-dividing cells and is not directly implicated in tumorigenesis. Despite their functional differences, the high homology of the two isoforms contributes to unwanted off-target effects of TOP2-directed therapies, sometimes leading to secondary cancer. Both isoforms can harbor naturally occurring or cancer-associated point mutations, which could confer altered sensitivity or resistance to chemotherapy agents. Using data from cancer genomic databases, we analyzed hotspot mutations of both isoforms found in human tumors and conducted a molecular analysis based on structural and functional data. We identified TOP2 variants in high-grade serous ovarian carcinoma, a malignancy frequently treated with TOP2-targeting agents, such as doxorubicin or etoposide. Our analysis emphasizes the importance of modeling somatic mutations to assess enzyme conformation and therapeutic response. Additionally, this review provides insights that underline the potential value of including TOP2A and TOP2B in companion diagnostic gene panels used in personalized oncology, notably in cancers where TOP2-directed agents are part of the standard therapy.