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

Ajore, Ram LU ; Raiser, David; McConkey, Marie E.; Jöud, Magnus LU ; Boidol, Bernd; Mar, Brenton G; Saksena, Gordon; Weinstock, David M; Armstrong, Scott and Ellis, Steven R, et al. (2017) In EMBO Molecular Medicine 9(4). p.498-507
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... (More)
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. (Less)
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keywords
cancer, ribosomal gene haploinsufficiency, ribosome function, protein p53, ribosome protein, short hairpin RNA, article, cancer cell line, cancer genetics, cancer tissue, cell growth, cell line, controlled study, disease association, gene deletion, gene mutation, gene silencing, genetic screening, haploinsufficiency, hemizygote, homozygote, human, human cell, malignant neoplasm, nonhuman, ribosomal protein gene, TP53 gene
in
EMBO Molecular Medicine
volume
9
issue
4
pages
10 pages
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • scopus:85014676014
  • wos:000398038200010
ISSN
1757-4684
DOI
10.15252/emmm.201606660
language
English
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yes
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e5d20fea-3bac-4cee-ad06-72059c6e7d1f
date added to LUP
2017-06-02 10:00:11
date last changed
2017-09-18 11:38:44
@article{e5d20fea-3bac-4cee-ad06-72059c6e7d1f,
  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.},
  author       = {Ajore, Ram and Raiser, David and McConkey, Marie E. and Jöud, Magnus and Boidol, Bernd and Mar, Brenton G and Saksena, Gordon and Weinstock, David M and Armstrong, Scott and Ellis, Steven R and Ebert, Benjamin L. and Nilsson, Björn},
  issn         = {1757-4684},
  keyword      = {cancer,ribosomal gene haploinsufficiency,ribosome function,protein p53,ribosome protein,short hairpin RNA,article,cancer cell line,cancer genetics,cancer tissue,cell growth,cell line,controlled study,disease association,gene deletion,gene mutation,gene silencing,genetic screening,haploinsufficiency,hemizygote,homozygote,human,human cell,malignant neoplasm,nonhuman,ribosomal protein gene,TP53 gene},
  language     = {eng},
  month        = {04},
  number       = {4},
  pages        = {498--507},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {EMBO Molecular Medicine},
  title        = {Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations},
  url          = {http://dx.doi.org/10.15252/emmm.201606660},
  volume       = {9},
  year         = {2017},
}