Transcription and DNA replication collisions lead to large tandem duplications and expose targetable therapeutic vulnerabilities in cancer.

IF 23.5 1区医学 Q1 ONCOLOGY

Nature cancer Pub Date : 2024-11-18 DOI:10.1038/s43018-024-00848-4

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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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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转录和 DNA 复制碰撞会导致大量串联重复，并暴露出癌症治疗的靶向漏洞。

尽管癌症中存在大量的体细胞结构变异（SV），但其形成的潜在分子机制仍不清楚。在本研究中，我们利用 6,193 例全基因组测序肿瘤研究了转录和 DNA 复制碰撞对基因组不稳定性的贡献。在对三个独立的泛癌队列中的强健SV特征进行去卷积后，我们在大型串联重复（TDs）中检测到了转录依赖性的复制链偏倚，即转录-复制碰撞（TRC）的预期足迹。大型串联重复体大量存在于女性多发的上消化道癌和前列腺癌中。它们与患者存活率低以及 TP53、CDK12 和 SPOP 的突变有关。使 CDK12 失活后，细胞会显示出明显更多的 TRC、R 环和大 TD。抑制 WEE1、CHK1 和 ATR 可选择性地抑制 CDK12 缺陷细胞的生长。我们的数据表明，癌症中的大 TD 是 TRC 的结果，它们的存在可用作预后和治疗的生物标记。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature cancer Medicine-Oncology

CiteScore

31.10

自引率

1.80%

发文量

129

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.