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.
| Original language | English |
|---|---|
| Pages (from-to) | 1519-1526 |
| Number of pages | 8 |
| Journal | Cell Reports |
| Volume | 5 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Dec 26 2013 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
Recessive cancer genes engage in negative genetic interactions with their functional paralogs. / D'Antonio, Matteo; Guerra, Rosalinda F.; Cereda, Matteo; Marchesi, Stefano; Montani, Francesca; Nicassio, Francesco; DiFiore, PierPaolo; Ciccarelli, Francesca D.
In: Cell Reports, Vol. 5, No. 6, 26.12.2013, p. 1519-1526.Research output: Contribution to journal › Article
}
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 - DiFiore, PierPaolo
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.
UR - http://www.scopus.com/inward/record.url?scp=84891038218&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891038218&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2013.11.033
DO - 10.1016/j.celrep.2013.11.033
M3 - Article
C2 - 24360954
AN - SCOPUS:84891038218
VL - 5
SP - 1519
EP - 1526
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 6
ER -