The transcriptomic architecture of common cancers reflects synthetic lethal interactions.
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Embargo End Date
ICR Authors
Authors
Haider, S
Brough, R
Madera, S
Iacovacci, J
Gulati, A
Wicks, A
Alexander, J
Pettitt, SJ
Tutt, ANJ
Lord, CJ
Brough, R
Madera, S
Iacovacci, J
Gulati, A
Wicks, A
Alexander, J
Pettitt, SJ
Tutt, ANJ
Lord, CJ
Document Type
Journal Article
Date
2025-03-13
Date Accepted
2025-01-28
Abstract
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 of BRCA1/2 synthetic lethal genes correlates with clinical outcome. Synthetic lethal genes that exhibit transcriptomic buffering also represent more robust synthetic lethal effects. These observations have implications for understanding how tumor cells tolerate TSG loss, in part explain transcriptomic architectures in cancer and provide insight into target selection.
Citation
Nature Genetics, 2025, 57 (3), pp. 522 - 529
Source Title
Nature Genetics
Publisher
NATURE PORTFOLIO
ISSN
1061-4036
eISSN
1546-1718
Collections
Research Team
Precision Oncology Lord
Directorate Breast Canc
Directorate Breast Canc