Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities
| Autor: | Ashton C. Berger, John P. Busanovich, Naomi Curimjee, Hope Wei, Sirano Dhe-Paganon, Jack A. Kosmicki, Meredith S. Brown, Andrew D. Cherniack, Rameen Beroukhim, Galen F. Gao, Brenton R. Paolella, Caitlin A. Nichols, Laura M. Urbanski, William J. Gibson |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
endocrine system diseases Molecular biology Somatic cell Science Loss of Heterozygosity General Physics and Astronomy DNA Primase Biology Article General Biochemistry Genetics and Molecular Biology Loss of heterozygosity 03 medical and health sciences 0302 clinical medicine RNA interference Neoplasms Cancer genomics medicine Humans Allele lcsh:Science neoplasms Gene Alleles Cancer Cell Proliferation Genetics Genes Essential Multidisciplinary Exosome Multienzyme Ribonuclease Complex Models Genetic RNA-Binding Proteins food and beverages General Chemistry medicine.disease digestive system diseases stomatognathic diseases 030104 developmental biology 030220 oncology & carcinogenesis Cancer cell Cancer research lcsh:Q |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. In tumors, hundreds of genes can undergo loss of heterozygosity (LOH). Here, the authors investigate the potential for this LOH as a class of non-driver cancer vulnerabilities. |
| Databáze: | OpenAIRE |
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