title: Recessive cancer genes engage in negative genetic interactions with their functional paralogs.
abstract: 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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: D'Antonio
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Rosalinda F
authors.initials: RF
authors.lastname: Guerra
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cereda
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Marchesi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Montani
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy; Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, 20139 Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicassio
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy; Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via di Rudinì 8, 20122 Milan, Italy.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy; Division of Cancer Studies, King's College London, London SE1 1UL, UK. Electronic address: francesca.ciccarelli@kcl.ac.uk.
authors.forename: Francesca D
authors.initials: FD
authors.lastname: Ciccarelli
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D005808:Genes, Recessive; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D004265:DNA Helicases; D009687:Nuclear Proteins; D014157:Transcription Factors; D000097584:DNA Methyltransferase 3B; C513384:CDH1 protein, human; C512197:CDH3 protein, human; C084011:SMARCA2 protein, human; C000619380:DNMT1 protein, human; C084108:SMARCA4 protein, human