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 language | English (US) |
---|---|
Article number | 100179 |
Pages (from-to) | 1885-1901 |
Number of pages | 17 |
Journal | Nature Cancer |
Volume | 5 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2024 |
Externally published | Yes |
ASJC Scopus subject areas
- Oncology
- Cancer Research