Recessive Cancer Genes Engage in Negative Genetic Interactions with Their Functional Paralogs

• Compensatory negative interactions occur between cancer genes and their paralogs
• These negative interactions suggest potential anticancer therapy targets
• SMARCA4 and CDH1 genetically interact with their paralogs
• The three human DNA methyltransferases have negative genetic interactions

SummaryCancer genetic heterogeneity offers a wide repertoire of molecular determinants to be screened as therapeutic targets. Here, we identify potential anticancer targets by exploiting negative genetic interactions between genes with driver loss-of-function mutations (recessive cancer genes) and their functionally redundant paralogs. We identify recessive genes with additional copies and experimentally test our predictions on three paralogous pairs. We confirm digenic negative interactions between two cancer genes (SMARCA4 and CDH1) and their corresponding paralogs (SMARCA2 and CDH3). Furthermore, we identify a trigenic negative interaction between the cancer gene DNMT3A, its functional paralog DNMT3B, and a third gene, DNMT1, which encodes the only other human DNA-methylase domain. Although our study does not exclude other causes of synthetic lethality, it suggests that functionally redundant paralogs of cancer genes could be targets in anticancer therapy.

Graphical AbstractFigure optionsDownload as PowerPoint slide