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

Author

Listed:
  • Caitlin A. Nichols

    (Departments of Cancer Biology
    Dana-Farber Cancer Institute and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • William J. Gibson

    (Broad Institute of MIT and Harvard
    Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School)

  • Meredith S. Brown

    (Departments of Cancer Biology
    Dana-Farber Cancer Institute and Harvard Medical School)

  • Jack A. Kosmicki

    (Massachusetts General Hospital and Harvard Medical School
    Broad Institute of MIT and Harvard
    Broad Institute of Harvard and MIT
    Harvard University)

  • John P. Busanovich

    (Departments of Cancer Biology
    Dana-Farber Cancer Institute and Harvard Medical School)

  • Hope Wei

    (Departments of Cancer Biology
    Dana-Farber Cancer Institute and Harvard Medical School)

  • Laura M. Urbanski

    (Departments of Cancer Biology
    Dana-Farber Cancer Institute and Harvard Medical School)

  • Naomi Curimjee

    (Departments of Cancer Biology
    Dana-Farber Cancer Institute and Harvard Medical School)

  • Ashton C. Berger

    (Dana-Farber Cancer Institute and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Galen F. Gao

    (Broad Institute of MIT and Harvard)

  • Andrew D. Cherniack

    (Dana-Farber Cancer Institute and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Sirano Dhe-Paganon

    (Departments of Cancer Biology
    Harvard Medical School)

  • Brenton R. Paolella

    (Departments of Cancer Biology
    Broad Institute of MIT and Harvard)

  • Rameen Beroukhim

    (Departments of Cancer Biology
    Dana-Farber Cancer Institute and Harvard Medical School
    Broad Institute of MIT and Harvard
    Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School)

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.

Suggested Citation

  • 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. Chernia, 2020. "Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16399-y
    DOI: 10.1038/s41467-020-16399-y
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