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EMBO Mol Med. 2017 Apr;9(4):498-507. doi: 10.15252/emmm.201606660.

Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations.

Author information

1
Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
2
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
3
Broad Institute, 7 Cambridge Center, Cambridge, MA, USA.
4
Dana-Farber Cancer Institute, Boston, MA, USA.
5
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY, USA.
7
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA benjamin_ebert@dfci.harvard.edu bjorn.nilsson@med.lu.se.
8
Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden benjamin_ebert@dfci.harvard.edu bjorn.nilsson@med.lu.se.

Abstract

Heterozygous inactivating mutations in ribosomal protein genes (RPGs) are associated with hematopoietic and developmental abnormalities, activation of p53, and altered risk of cancer in humans and model organisms. Here we performed a large-scale analysis of cancer genome data to examine the frequency and selective pressure of RPG lesions across human cancers. We found that hemizygous RPG deletions are common, occurring in about 43% of 10,744 cancer specimens and cell lines. Consistent with p53-dependent negative selection, such lesions are underrepresented in TP53-intact tumors (P ≪ 10-10), and shRNA-mediated knockdown of RPGs activated p53 in TP53-wild-type cells. In contrast, we did not see negative selection of RPG deletions in TP53-mutant tumors. RPGs are conserved with respect to homozygous deletions, and shRNA screening data from 174 cell lines demonstrate that further suppression of hemizygously deleted RPGs inhibits cell growth. Our results establish RPG haploinsufficiency as a strikingly common vulnerability of human cancers that associates with TP53 mutations and could be targetable therapeutically.

KEYWORDS:

cancer; ribosomal gene haploinsufficiency; ribosome function

PMID:
28264936
PMCID:
PMC5376749
DOI:
10.15252/emmm.201606660
[Indexed for MEDLINE]
Free PMC Article

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