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

TY - JOUR

T1 - Recessive cancer genes engage in negative genetic interactions with their functional paralogs

AU - D'Antonio, Matteo

AU - Guerra, Rosalinda F

AU - Cereda, Matteo

AU - Marchesi, Stefano

AU - Montani, Francesca

AU - Nicassio, Francesco

AU - Di Fiore, Pier Paolo

AU - Ciccarelli, Francesca D

PY - 2013/12/26

Y1 - 2013/12/26

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2013.11.033

DO - 10.1016/j.celrep.2013.11.033

M3 - Article

C2 - 24360954

SN - 2211-1247

VL - 5

SP - 1519

EP - 1526

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - N/A

ER -