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Studying large genomic deletions with MACHETE

Nature Reviews Cancer volume 23, page 271 (2023)Cite this article

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Cancer genomes are characterized by the presence of copy number alterations (CNAs), which are recurrent events that increase or decrease the dosage of specific regions of DNA. CNAs can affect up to 30% of a cancer cell genome and are associated with poor clinical outcomes. Among CNAs, genomic deletions are the most recurrent events, yet their functional effects remain largely unknown. This paucity of mechanistic data is due to the complexity of modelling megabase-sized deletions, where most approaches have low efficiency and are not readily scalable.

To address this major gap in cancer genetics, we developed Molecular Alteration of Chromosomes with Engineered Tandem Elements (MACHETE). MACHETE is a two-step approach: first, it involves the insertion of a bicistronic cassette consisting of positive and negative selection into the locus of interest, via CRISPR–Cas9-mediated homology driven repair. Second, single-guide RNAs are introduced to create the deletion event, which is then followed by strong negative selection. Only cells that eliminated the locus of interest remove the suicide cassette, thus greatly enriching for cells with the intended deletion.

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References

Original article

  • Barriga, F. M. et al. MACHETE identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis. Nat. Cancer 3, 1367–1385 (2022)

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Authors and Affiliations

  1. Cancer Genome Engineering Lab, VHIO, Barcelona, Spain

    Francisco M. Barriga

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  1. Francisco M. Barriga
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Correspondence to Francisco M. Barriga.

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The author declares no competing interests.

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Barriga, F.M. Studying large genomic deletions with MACHETE. Nat Rev Cancer 23, 271 (2023). https://doi.org/10.1038/s41568-023-00561-x

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  • DOI: https://doi.org/10.1038/s41568-023-00561-x

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