biostudies-literatureHaider SCancer Research UKBreast Cancer Now522-529https://www.ebi.ac.uk/biostudies/studies/S-EPMC11906352biostudies-literatureUnknown57(3)To maintain cell fitness, deleterious genetic alterations are buffered by compensatory changes in additional genes. In cancer, buffering processes could be targeted by synthetic lethality. However, despite the large-scale identification of synthetic lethal effects in preclinical models, evidence that these operate clinically is limited. This impedes the application of synthetic lethal approaches. By integrating molecular profiling data from >9,000 cancers with synthetic lethal screens, we show that transcriptomic buffering of tumor suppressor gene (TSG) loss by hyperexpression of synthetic lethal partners is a common phenomenon, extending to multiple TSGs and histotypes. Transcriptomic buffering is also notable in cancers that phenocopy TSG loss, such as BRCAness cancers, where expression Nature geneticsThe transcriptomic architecture of common cancers reflects synthetic lethal interactions.PMC11906352DRCRPGNov21y100001CTR-Q5-Y5Pettitt SJLord CJBrough RMadera SHaider SWicks AGulati AAlexander JTutt ANJIacovacci JfalseThe transcriptomic architecture of common cancers reflects synthetic lethal interactions.To maintain cell fitness, deleterious genetic alterations are buffered by compensatory changes in additional genes. In cancer, buffering processes could be targeted by synthetic lethality. However, despite the large-scale identification of synthetic lethal effects in preclinical models, evidence that these operate clinically is limited. This impedes the application of synthetic lethal approaches. By integrating molecular profiling data from >9,000 cancers with synthetic lethal screens, we show that transcriptomic buffering of tumor suppressor gene (TSG) loss by hyperexpression of synthetic lethal partners is a common phenomenon, extending to multiple TSGs and histotypes. Transcriptomic buffering is also notable in cancers that phenocopy TSG loss, such as BRCAness cancers, where expression 2025-01-01T00:00:00Z2025 Mar2026-06-01T15:11:04.327Z2025-04-06T11:39:18.033ZS-EPMC119063524003305610.1038/s41588-025-02108-2