2. Academic Validation
  3. The transcriptomic architecture of common cancers reflects synthetic lethal interactions

The transcriptomic architecture of common cancers reflects synthetic lethal interactions

  • Nat Genet. 2025 Mar;57(3):522-529. doi: 10.1038/s41588-025-02108-2.
Syed Haider 1,  Rachel Brough # 2 3,  Santiago Madera # 2,  Jacopo Iacovacci 2,  Aditi Gulati 2,  Andrew Wicks 2 3,  John Alexander 2,  Stephen J Pettitt 4 5,  Andrew N J Tutt 6,  Christopher J Lord 7 8
Affiliations

Affiliations

  • 1 Breast Cancer Now Toby Robins Breast Cancer Research Centre, London, UK. Syed.Haider@icr.ac.uk.
  • 2 Breast Cancer Now Toby Robins Breast Cancer Research Centre, London, UK.
  • 3 CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
  • 4 Breast Cancer Now Toby Robins Breast Cancer Research Centre, London, UK. Stephen.Pettitt@icr.ac.uk.
  • 5 CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK. Stephen.Pettitt@icr.ac.uk.
  • 6 Breast Cancer Now Toby Robins Breast Cancer Research Centre, London, UK. Andrew.Tutt@icr.ac.uk.
  • 7 Breast Cancer Now Toby Robins Breast Cancer Research Centre, London, UK. Chris.Lord@icr.ac.uk.
  • 8 CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK. Chris.Lord@icr.ac.uk.
  • # Contributed equally.
PMID: 40033056 DOI: 10.1038/s41588-025-02108-2
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.

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