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.
Highlights
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
Because recent studies have shown that Ribosomal protein genes (RPGs) haploinsufficiency activates p53 in ribosomopathies (Narla & Ebert, 2010; Raiser et al, 2014) and the pathobiology of ribosomopathies can be alleviated by p53 inhibition (Volarevic et al, 2000; Sulic et al, 2005; Fumagalli et al, 2009; Barlow et al, 2010; Dutt et al, 2011; Jaako et al, 2011), we hypothesized that inactivation of RPGs could lead to negative selection unless the cells have mutated TP53, and, looked for associations between inactivating RPG lesions and TP53 mutation
Consistent with negative selection, further analyses revealed an underrepresentation of RPG deletions in TP53-intact tumors, whereas we did not see any signs of negative selection in TP53-mutant tumors
Summary
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. 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 ( 10À10), and shRNA-mediated knockdown of RPGs activated p53 in TP53-wild-type cells. We did not see negative selection of RPG deletions in TP53-mutant tumors. Our results establish RPG haploinsufficiency as a strikingly common vulnerability of human cancers that associates with TP53 mutations and could be targetable therapeutically
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