title: Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert withTP53mutations.
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 inTP53-intact tumors (P≪ 10-10), and shRNA-mediated knockdown of RPGs activated p53 inTP53-wild-type cells. In contrast, we did not see negative selection of RPG deletions inTP53-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 withTP53mutations and could be targetable therapeutically.
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Ram
authors.initials: R
authors.lastname: Ajore
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Raiser
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: McConkey
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Jöud
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Bernd
authors.initials: B
authors.lastname: Boidol
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Brenton
authors.initials: B
authors.lastname: Mar
authors.affiliation: Broad Institute, 7 Cambridge Center, Cambridge, MA, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Saksena
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Armstrong
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ellis
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA benjamin_ebert@dfci.harvard.edu bjorn.nilsson@med.lu.se.|Broad Institute, 7 Cambridge Center, Cambridge, MA, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden benjamin_ebert@dfci.harvard.edu bjorn.nilsson@med.lu.se.|Broad Institute, 7 Cambridge Center, Cambridge, MA, USA.
authors.forename: Björn
authors.identifier: 0000-0001-5542-0254
authors.initials: B
authors.lastname: Nilsson
mesh_terms: D045744:Cell Line, Tumor; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000473:pathology*; D012269:Ribosomal Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D012269:Ribosomal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: cancer; ribosomal gene haploinsufficiency; ribosome function