Open AccessDeletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP 53 mutations
Author(s) -
Ajore Ram,
Raiser David,
McConkey Marie,
Jöud Magnus,
Boidol Bernd,
Mar Brenton,
Saksena Gordon,
Weinstock David M,
Armstrong Scott,
Ellis Steven R,
Ebert Benjamin L,
Nilsson Björn
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201606660
Subject(s) - gene , ribosomal protein , ribosomal rna , biology , cancer , genetics , mutation , microbiology and biotechnology , computational biology , ribosome , rna
Heterozygous inactivating mutations in ribosomal protein genes ( RPG s) 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 TP 53 ‐intact tumors ( P ≪ 10 −10 ), and sh RNA ‐mediated knockdown of RPG s activated p53 in TP 53 ‐wild‐type cells. In contrast, we did not see negative selection of RPG deletions in TP 53 ‐mutant tumors. RPG s are conserved with respect to homozygous deletions, and sh RNA screening data from 174 cell lines demonstrate that further suppression of hemizygously deleted RPG s inhibits cell growth. Our results establish RPG haploinsufficiency as a strikingly common vulnerability of human cancers that associates with TP 53 mutations and could be targetable therapeutically.