Open AccessRecurrent mutations in topoisomerase IIα cause a previously undescribed mutator phenotype in human cancers
Author(s) -
Arnoud Boot,
Mo Liu,
Nicole Stantial,
Viraj Shah,
Willie Yu,
Karin C. Nitiss,
John L. Nitiss,
Sue Jinks-Robertson,
Steve Rozen
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2114024119
Subject(s) - topoisomerase , biology , genetics , mutation , phenotype , gene , somatic cell , indel , dna , cancer research , single nucleotide polymorphism , genotype
Significance Topoisomerases are crucial for genome maintenance and are targets for several chemotherapeutic agents. While anticancer drugs targeting topoisomerases can lead to secondary malignancies, there have been no descriptions of genetic defects in topoisomerases having roles in cancer development. Here we show that a somatic topoisomerase IIα mutation found in human tumors results in a mutator phenotype. We show that this mutation and the concomitant mutational signature, which we call ID_TOP2α, are associated with genomic rearrangements and with potentially oncogenic indel mutations in known driver genes. Our results shed new light on topoisomerase IIα function, on repair of trapped cleavage complexes, and on a likely oncogenic role for topoisomerases.