Yang Yang, Michelle L Badura, Patrick C O'Leary, Henry M Delavan, Troy M Robinson, Emily A Egusa, Xiaoming Zhong, Jason T Swinderman, Haolong Li, Meng Zhang, Minkyu Kim, Alan Ashworth, Felix Y Feng, Jonathan Chou, Lixing Yang
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Transcription and DNA replication collisions lead to large tandem duplications and expose targetable therapeutic vulnerabilities in cancer.
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.
期刊介绍：
Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates.
Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale.
In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.
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