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Published on: March 7, 2019
Recessive cancer genes engage in negative genetic interactions with their functional paralogs
Matteo D'Antonio1, Rosalinda F Guerra1, Matteo Cereda1
1Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
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.
Insights
Identifying cancer targets by exploiting negative genetic interactions between driver cancer genes and their redundant paralogs offers new therapeutic strategies. This research highlights functionally redundant paralogs as potential anticancer targets.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Cancer genetic heterogeneity presents numerous molecular targets for therapy.
- Exploiting genetic interactions is a promising strategy for identifying novel therapeutic targets.
Purpose of the Study:
- To identify potential anticancer targets by investigating negative genetic interactions.
- To explore the therapeutic potential of functionally redundant paralogs of cancer genes.
Main Methods:
- Identification of recessive cancer genes with driver loss-of-function mutations.
- Analysis of negative genetic interactions between cancer genes and their functionally redundant paralogs.
- Experimental validation of predicted interactions in paralogous gene pairs.
Main Results:
- Confirmed digenic negative interactions between cancer genes (SMARCA4, CDH1) and their paralogs (SMARCA2, CDH3).
- Identified a trigenic negative interaction involving the cancer gene DNMT3A, its paralog DNMT3B, and DNMT1.
- Demonstrated that functionally redundant paralogs of cancer genes can be targeted for anticancer therapy.
Conclusions:
- Functionally redundant paralogs of cancer genes represent viable targets for anticancer therapies.
- Negative genetic interactions provide a framework for discovering novel synthetic lethal interactions in cancer.
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