Recessive cancer genes engage in negative genetic interactions with their functional paralogs

Matteo D'Antonio, Rosalinda F. Guerra, Matteo Cereda, Stefano Marchesi, Francesca Montani, Francesco Nicassio, PierPaolo DiFiore, Francesca D. Ciccarelli

Research output: Contribution to journalArticlepeer-review


Cancer 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.

Original languageEnglish
Pages (from-to)1519-1526
Number of pages8
JournalCell Reports
Issue number6
Publication statusPublished - Dec 26 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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