The transcriptomic architecture of common cancers reflects synthetic lethal interactions

To maintain cell fitness, the deleterious effects of gene defects are often buffered by compensatory changes in additional genes. In cancer, these buffering processes could, in principle, be targeted for therapy exploiting the principle of synthetic lethality (SL). However, despite the large-scale identification of SL effects in pre-clinical models, evidence that these operate in the clinical disease is limited to a small number of examples, a problem that impedes the wider application of the concept. Using an integrated analysis of in vitro synthetic lethal screens in cell models with the molecular profiles of >9,000 cancers, we show that transcriptomic buffering of tumour suppressor gene (TSG) loss by hyperexpression of SL partners is a common phenomenon in human cancers and extends to multiple TSGs and cancer histologies. This effect is also seen in cancers that phenocopy those with specific TSG loss, such as cancers with BRCAness, where a metagene of hyperexpressed BRCA1/2 SL genes correlates with clinical outcome and therapy response. These observations have implications for understanding how tumour cells tolerate TSG loss, in part explain the transcriptomic architecture of cancers, and finally highlight a series of pre-clinically identified SL effects that are represented by buffering relationships in human cancers.