Large tandem duplications in cancer result from transcription and DNA replication collisions.
Large tandem duplications in cancer result from transcription and DNA replication collisions.
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癌症中的大量串联重复是由转录和 DNA 复制碰撞引起的。
DOI：
10.1101/2023.05.17.23290140
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Yang,Lixing
中科院分区：
文献类型：
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作者：
Yang,Yang;Badura,MichelleL;O'Leary,PatrickC;Delavan,HenryM;Robinson,TroyM;Egusa,EmilyA;Zhong,Xiaoming;Swinderman,JasonT;Li,Haolong;Zhang,Meng;Kim,Minkyu;Ashworth,Alan;Feng,FelixY;Chou,Jonathan;Yang,Lixing
尽管在癌症中存在丰富的体细胞结构变异(SVS)，但其形成的潜在分子机制仍不清楚。在这里，我们使用6,193个全基因组测序的肿瘤来研究转录和DNA复制碰撞对基因组不稳定性的贡献。在三个独立的泛癌队列中解卷出稳健的SV信号后，我们在大型串联复制(TD)中检测到转录依赖的复制链偏差，即预期的转录-复制碰撞(TRC)足迹。女性聚集型、上胃肠道癌和前列腺癌中大量存在较大的TD。它们与患者较差的生存和TP53、CDK12和SPOP的突变有关。在CDK12失活后，细胞显示明显更多的TRC、R-环和大的TD。抑制G2/M检查点蛋白，如WEE1、CHK1和ATR，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TDS是由于TRCs而形成的，它们的存在可以作为预后和治疗的生物标记物。
Despite the abundance of somatic structural variations (SVs) in cancer, the underlying molecular mechanisms of their formation remain unclear. Here, we use 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 detect 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 G2/M checkpoint proteins, such as WEE1, CHK1, and ATR, selectively inhibits the growth of cells deficient in CDK12. Our data suggest that large TDs in cancer form due to TRCs, and their presence can be used as a biomarker for prognosis and treatment.