Topoisomerase IIb binding delineates localized mutational processes and driver mutations in cancer genomes
Bibliographic record
Abstract
Type-II topoisomerases resolve topological stress in DNA through double-strand breaks. While topoisomerases are chemotherapy targets linked to therapy-related genotoxicity, TOP2B is uniquely positioned to influence mutagenesis through its activity in non-dividing cells and sensitivity to topoisomerase poisons. To investigate this, we generated DNA-binding maps of TOP2B, CTCF, and RAD21 in human cancer samples and analyzed these for driver mutations and mutational processes across 6500 whole cancer genomes. TOP2B-CTCF-RAD21 and TOP2B-RAD21 sites are enriched in somatic mutations and structural variants, particularly at sites with evolutionary conservation, high transcription and long-range chromatin interactions. TOP2B binds driver genes such as TP53, MYC, FOXA1, and VHL, and many frequently mutated non-coding regions. We show that one non-coding TOP2B-bound element at the non-coding RNA gene RMRP drives tumor initiation and growth in vivo. Our study highlights TOP2B as a safeguard of genome integrity and a marker of mutational processes and hotspots in cancer, underscoring implications for cancer genomics research. Topoisomerases resolve topological DNA stress via double-strand breaks and are established targets of cancer chemotherapies. Here, the authors link genomic binding of TOP2B with localized mutational processes in cancer genomes that include prominent driver genes and translocation hotspots.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".