Large tandem duplications in cancer result from transcription and DNA replication collision
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 or suppressing CDK12, cells display significantly more TRCs and R-loops. Inhibition of WEE1, a cell cycle regulator that promotes DNA repair, selectively inhibits the growth of cells with loss of CDK12. Our data suggest that large TDs in cancer form due to TRC, and their presence can be used as a biomarker for prognosis and treatment. We are depositing the whole exome sequencing (WES) data for C42B Control and CDK12 KO clones presented in the paper.