Recurrent mutations in topoisomerase 2a cause a novel mutator phenotype in human cancers

Topoisomerases are essential for genome stability. Here, we link the p.K743N mutation in topoisomerase TOP2A to a previously undescribed mutator phenotype in human cancers. This phenotype primarily generates a distinctive pattern of duplications of 2 to 4 base pairs and deletions of 6 to 8 base pairs, which we call ID\_TOP2A. All tumors carrying the TOP2A p.K743N mutation showed ID\_TOP2A, which was absent in all of 12,269 other tumors. We also report evidence of structural variation associated with TOP2A p.K743N. All tumors with ID\_TOP2A mutagenesis had several indels in known cancer genes, including frameshift mutations in PTEN and TP53 and an in-frame activating mutation in BRAF . Thus, ID\_TOP2A mutagenesis almost certainly contributed to tumorigenesis in these tumors. This is the first report of topoisomerase-associated mutagenesis in human cancers, and sheds further light on TOP2A’s role in genome maintenance. We also postulate that tumors showing ID_TOP2A mutagenesis might be especially sensitive to topoisomerase inhibitors. ### Competing Interest Statement The authors have declared no competing interest.