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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number100179
Pages (from-to)1885-1901
Number of pages17
JournalNature Cancer
Volume5
Issue number12
DOIs
StatePublished - Dec 2024
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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