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Synthetic lethality and cancer

Nature Reviews Genetics volume 18, pages 613–623 (2017)Cite this article

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Key Points

  • Synthetic lethal genetic interactions with tumour-specific mutations may be exploited to develop anticancer therapeutics.

  • Synthetic dosage lethality and conditional synthetic lethality can expand the scope of conventional synthetic lethal studies.

  • Genetic interaction networks in model organisms provide a framework for screening cancer-relevant candidate synthetic lethal interactions in human cells.

  • Large-scale screening for cancer gene-specific synthetic lethal candidates in human cells has progressed through advances in RNA interference and the CRISPR–Cas9 system.

  • The CRISPR–Cas9 technology is a versatile platform for exploring genetic networks and synthetic lethal interaction phenotypes.

  • The search for synthetic lethality-based therapeutic strategies could be enhanced by integrating synthetic lethal interactions from three distinct sources: model organism genetic networks, human high-throughput screening and synthetic lethal predictions from statistical genetics.

Abstract

A synthetic lethal interaction occurs between two genes when the perturbation of either gene alone is viable but the perturbation of both genes simultaneously results in the loss of viability. Key to exploiting synthetic lethality in cancer treatment are the identification and the mechanistic characterization of robust synthetic lethal genetic interactions. Advances in next-generation sequencing technologies are enabling the identification of hundreds of tumour-specific mutations and alterations in gene expression that could be targeted by a synthetic lethality approach. The translation of synthetic lethality to therapy will be assisted by the synthesis of genetic interaction data from model organisms, tumour genomes and human cell lines.

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Figure 1: The concept of synthetic lethality.
Figure 2: The concept of conditional synthetic lethality.
Figure 3: A cross-platform approach for discovering clinically relevant synthetic lethal interactions.
Figure 4: Strategy for large-scale synthetic lethality screens for a gene of interest in human cells.

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Acknowledgements

P.H. is a senior fellow in the Genetic Networks program at the Canadian Institute for Advanced Research.

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  1. Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, V6T 1Z4, British Columbia, Canada

    Nigel J. O'Neil, Melanie L. Bailey & Philip Hieter

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  1. Nigel J. O'Neil
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Correspondence to Philip Hieter.

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Synthetic lethality

A synthetic lethal interaction occurs between two genes when a perturbation (a mutation, RNA interference knockdown or inhibition) that affects either gene alone is viable but the perturbation of both genes simultaneously is lethal.

Non-homologous end-joining

(NHEJ). The repair of double-strand DNA breaks by direct ligation without the use of a homologous template.

Homologous recombination

The exchange of nucleotide sequences between identical (or near identical) DNA molecules. Homologous recombination is the most common form of homology-directed repair of double-strand DNA breaks.

Genetic interaction network

A genetic interaction occurs when the perturbation of one or more genes affects the phenotype of another gene alteration. A genetic interaction network defines the functional relationship between many genes.

Orthologue

Genes in different species that are originated from a single gene of the last common ancestor.

Modules

Groups of genes or proteins that act together in a common cellular function.

Synthetic sickness

A synthetic sickness interaction occurs between two genes when a perturbation (a mutation, RNA interference knockdown or inhibition) that affects either gene alone is viable but the disruption of both genes simultaneously results in a reduction of viability.

Driver mutations

Mutations that confer a selective growth advantage to a cancer or a pre-cancerous cell.

Isogenic

Organisms or cell lines that contain identical or nearly identical genotypes.

Heterogeneity

In a cell line or tumour, the diversity of genotypes within the population.

Gene essentiality profiles

Sets of genes required for proliferation or viability in the context of a single cell line or tumour type.

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O'Neil, N., Bailey, M. & Hieter, P. Synthetic lethality and cancer. Nat Rev Genet 18, 613–623 (2017). https://doi.org/10.1038/nrg.2017.47

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