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Updated: Oct 11, 2025
Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
Published on: May 30, 2025
Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers
Solip Park1, Fran Supek2,3, Ben Lehner4,5,6
1Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. solippark@cnio.es.
Abstract:
The classic two-hit model posits that both alleles of a tumor suppressor gene (TSG) must be inactivated to cause cancer. In contrast, for some oncogenes and haploinsufficient TSGs, a single genetic alteration can suffice to increase tumor fitness. Here, by quantifying the interactions between mutations and copy number alterations (CNAs) across 10,000 tumors, we show that many cancer genes actually switch between acting as one-hit or two-hit drivers. Third order genetic interactions identify the causes of some of these switches in dominance and dosage sensitivity as mutations in other genes in the same biological pathway. The correct genetic model for a gene thus depends on the other mutations in a genome, with a second hit in the same gene or an alteration in a different gene in the same pathway sometimes representing alternative evolutionary paths to cancer.
Insights
Cancer gene behavior isn't fixed; it can act as a one-hit or two-hit driver depending on other genetic mutations. This suggests alternative evolutionary paths to cancer driven by pathway interactions.
Area of Science:
- Genomics
- Cancer Biology
- Computational Biology
Background:
- The traditional cancer model requires two gene "hits" to inactivate tumor suppressor genes (TSGs).
- Some genes, like oncogenes and haploinsufficient TSGs, can drive cancer with just one genetic alteration.
- Understanding gene behavior in cancer evolution is crucial for targeted therapies.
Purpose of the Study:
- To investigate how genetic interactions influence cancer gene behavior.
- To determine if cancer genes can act as either one-hit or two-hit drivers.
- To identify the genomic factors causing shifts in gene dominance and dosage sensitivity.
Main Methods:
- Analysis of mutation and copy number alteration (CNA) data from 10,000 tumors.
- Quantification of genetic interactions between mutations and CNAs.
- Identification of third-order genetic interactions to pinpoint causes of altered gene behavior.
Main Results:
- Many cancer genes switch between one-hit and two-hit driver roles.
- Mutations in other genes within the same biological pathway can cause these switches.
- Gene behavior is context-dependent, influenced by the overall genomic landscape.
Conclusions:
- The "hit" model for cancer genes is not absolute and depends on genomic context.
- Pathway interactions provide alternative evolutionary routes to cancer development.
- This finding refines our understanding of cancer genetics and potential therapeutic strategies.
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