ArticleNature cancer2024
Transcription and DNA replication collisions lead to large tandem duplications and expose targetable therapeutic vulnerabilities in cancer.
Article in Nature cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed.
- Polymerase face-off: emerging concepts in transcription-replication coordination.EMBO reports · 2026Review
- Pan-cancer multi-omics analysis identifies SYNGR4 as a novel clinical prognostic biomarker and therapeutic target in lung adenocarcinoma.Discover oncology · 2026Article
- TONSOKU prevents the formation of large tandem duplications and restrains ATR-WEE1 checkpoint activation.Nature communications · 2026Article
- Construction of a survival model for predicting biochemical recurrence of prostate cancer based on propionate metabolism-related genes.Translational andrology and urology · 2026Article
- Decoding the Genomic and Functional Landscape of Emerging Subtypes in Ovarian Cancer.Cancer discovery · 2025Article
- Panorama of Chromosomal Instability in Lung Cancer.medRxiv : the preprint server for health sciences · 2025Article
- Atypical R-loops in cancer: decoding molecular chaos for therapeutic gain.Journal of translational medicine · 2025Review
- DNA2 protein destruction dictates DNA hyperexcision, cGAS-STING activation, and innate immune response in CDK12-deregulated cancers.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12.Nature communications · 2025Article
- Complex rearrangements fuel ERNature · 2025Article
- Mechanisms of tandem duplication in the cancer genome.DNA repair · 2025Review
- Synthetic Lethal Targeting of CDK12-Deficient Prostate Cancer with PARP Inhibitors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Somatic structural variation signatures in pediatric brain tumors.Cell reports · 2023Article
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15 authors.
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Abstract
Despite the abundance of somatic structural variations (SVs) in cancer, the underlying molecular mechanisms of their formation remain unclear. In the present study, we used 6,193 whole-genome sequenced tumors to study the contributions of transcription and DNA replication collisions to genome instability. After deconvoluting robust SV signatures in three independent pan-cancer cohorts, we detected transcription-dependent, replicated-strand bias, the expected footprint of transcription-replication collision (TRC), in large tandem duplications (TDs). Large TDs are abundant in female-enriched, upper gastrointestinal tract and prostate cancers. They are associated with poor patient survival and mutations in TP53, CDK12 and SPOP. Upon inactivating CDK12, cells display significantly more TRCs, R-loops and large TDs. Inhibition of WEE1, CHK1 and ATR selectively inhibits the growth of cells deficient in CDK12. Our data suggest that large TDs in cancer form as a result of TRCs and their presence can be used as a biomarker for prognosis and treatment.
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