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2017 ; 9
(4
): 498-507
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Deletion of ribosomal protein genes is a common vulnerability in human cancer,
especially in concert with TP53 mutations
#MMPMID28264936
Ajore R
; Raiser D
; McConkey M
; Jöud M
; Boidol B
; Mar B
; Saksena G
; Weinstock DM
; Armstrong S
; Ellis SR
; Ebert BL
; Nilsson B
EMBO Mol Med
2017[Apr]; 9
(4
): 498-507
PMID28264936
show ga
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.