Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities

Nat Commun. 2020 May 20;11(1):2517. doi: 10.1038/s41467-020-16399-y.


Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. Hundreds to thousands of non-driver genes undergo loss of heterozygosity (LOH) events per tumor, generating discrete differences between tumor and normal cells. Here we interrogate LOH of polymorphisms in essential genes as a novel class of therapeutic targets. We hypothesized that monoallelic inactivation of the allele retained in tumors can selectively kill cancer cells but not somatic cells, which retain both alleles. We identified 5664 variants in 1278 essential genes that undergo LOH in cancer and evaluated the potential for each to be targeted using allele-specific gene-editing, RNAi, or small-molecule approaches. We further show that allele-specific inactivation of either of two essential genes (PRIM1 and EXOSC8) reduces growth of cells harboring that allele, while cells harboring the non-targeted allele remain intact. We conclude that LOH of essential genes represents a rich class of non-driver cancer vulnerabilities.

MeSH terms

  • Alleles
  • Cell Proliferation
  • DNA Primase / genetics
  • Exosome Multienzyme Ribonuclease Complex / genetics
  • Genes, Essential*
  • Humans
  • Loss of Heterozygosity*
  • Models, Genetic
  • Neoplasms / genetics*
  • Neoplasms / physiopathology
  • RNA-Binding Proteins / genetics


  • RNA-Binding Proteins
  • DNA Primase
  • PRIM1 protein, human
  • EXOSC8 protein, human
  • Exosome Multienzyme Ribonuclease Complex