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

Caitlin A Nichols; William J Gibson; Meredith S Brown; Jack A Kosmicki; John P Busanovich; Hope Wei; Laura M Urbanski; Naomi Curimjee; Ashton C Berger; Galen F Gao; Andrew D Cherniack; Sirano Dhe-Paganon; Brenton R Paolella; Rameen Beroukhim

doi:10.1038/s41467-020-16399-y

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.

Authors

Caitlin A Nichols^{1

2

3}, William J Gibson^{3

4}, Meredith S Brown^{1

2}, Jack A Kosmicki^{5

6

7

8}, John P Busanovich^{1

2}, Hope Wei^{1

2}, Laura M Urbanski^{1

2}, Naomi Curimjee^{1

2}, Ashton C Berger^{2

3}, Galen F Gao³, Andrew D Cherniack^{2

3}, Sirano Dhe-Paganon^{1

9}, Brenton R Paolella^{10

11}, Rameen Beroukhim^{12

13

14

15}

Affiliations

¹ Departments of Cancer Biology, Boston, MA, USA.
² Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁴ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
⁵ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
⁶ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁷ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
⁸ Program in Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA, 02138, USA.
⁹ Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
¹⁰ Departments of Cancer Biology, Boston, MA, USA. paolella@broadinstitute.org.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. paolella@broadinstitute.org.
¹² Departments of Cancer Biology, Boston, MA, USA. rameen_beroukhim@dfci.harvard.edu.
¹³ Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA. rameen_beroukhim@dfci.harvard.edu.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. rameen_beroukhim@dfci.harvard.edu.
¹⁵ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA. rameen_beroukhim@dfci.harvard.edu.

Abstract

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

Substances

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

Grants and funding

T32 HG002295/HG/NHGRI NIH HHS/United States