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

Research output: Contribution to journalArticle

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.

Details

Authors
Organisations
External organisations
  • Dana-Farber Cancer Institute
  • Memorial Sloan-Kettering Cancer Center
  • Harvard Medical School
  • Broad Institute
  • University of Louisville
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

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
Original languageEnglish
Pages (from-to)498-507
Number of pages10
JournalEMBO Molecular Medicine
Volume9
Issue number4
Publication statusPublished - 2017 Apr 1
Publication categoryResearch
Peer-reviewedYes

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