Distinctive indel mutational signature in tumors carrying TOP2A p.K743N
Boot, A.; Rozen, S. G.
Show abstract
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 TOP2As role in genome maintenance. We also postulate that tumors showing ID_TOP2A mutagenesis might be especially sensitive to topoisomerase inhibitors.
Matching journals
The top 13 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2 93%
- A survey of human cancer-germline genes: linking X chromosome localization, DNA methylation and sex-biased expression in early embryos 92%
- Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells 92%
Similar papers in this journal
- Transcriptomic analyses of MYCN-regulated genes in anaplastic Wilms' tumour cell lines reveals oncogenic pathways and potential therapeutic vulnerabilities 92%
- Alternative polyadenylation characterizes epithelial and fibroblast phenotypic heterogeneity in pancreatic ductal adenocarcinoma 92%
- Sex biases in cancer and autoimmune disease incidence are strongly positively correlated with mitochondrial gene expression across human tissues 92%
Similar papers in this journal
- Saturation-scale functional evidence supports clinical variant interpretation in Lynch Syndrome 93%
- Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs 93%
- Single cell decoding of drug induced transcriptomic reprogramming in triple negative breast cancers 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.