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

Abstract

Topoisomerases are essential for genome stability. Here we link a rare recurrent hotspot mutation, p.K743N, in topoisomerase TOP2A to a unique pattern of small insertions and deletions (indels) in human cancers. This pattern consists mainly of duplications of 2 to 4 base pairs and deletions of 6 to 8 base pairs. These resemble indel mutational signatures ID17 and ID8, which until now had unknown causes. In total, we identified 7 tumors carrying TOP2A p.K743N, all of which showed both ID8 and ID17 characteristics. Furthermore, ID17 was absent from all 12,269 tumors lacking this mutation. We also report evidence of structural variation associated with TOP2A p.K743N. We propose that TOP2A p.K743 induces a novel mutational signature incorporating ID17 and features of ID8, which we call ID_TOP2A. This is the first report of topoisomerase-associated mutagenesis in human cancers, shedding further light on TOP2A's crucial role in genome maintenance and importance in cancer. Main textType II topoisomerases are essential for genome maintenance. They untangle DNA by creating and then repairing double strand breaks to allow entangled DNA strands to pass