Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations
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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606660 |
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| author | Ram Ajore David Raiser Marie McConkey Magnus Jöud Bernd Boidol Brenton Mar Gordon Saksena David M Weinstock Scott Armstrong Steven R Ellis Benjamin L Ebert Björn Nilsson |
| author_facet | Ram Ajore David Raiser Marie McConkey Magnus Jöud Bernd Boidol Brenton Mar Gordon Saksena David M Weinstock Scott Armstrong Steven R Ellis Benjamin L Ebert Björn Nilsson |
| author_sort | Ram Ajore |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3e6cbff888654a0ea0a66eb8b06bbc66 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-3e6cbff888654a0ea0a66eb8b06bbc662025-08-20T03:46:11ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-03-019449850710.15252/emmm.201606660Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutationsRam Ajore0David Raiser1Marie McConkey2Magnus Jöud3Bernd Boidol4Brenton Mar5Gordon Saksena6David M Weinstock7Scott Armstrong8Steven R Ellis9Benjamin L Ebert10Björn Nilsson11Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund UniversityDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolHematology and Transfusion Medicine, Department of Laboratory Medicine, Lund UniversityDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolBroad Institute, 7 Cambridge CenterDana‐Farber Cancer InstituteMemorial Sloan Kettering Cancer CenterDepartment of Biochemistry and Molecular Biology, University of LouisvilleDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical SchoolHematology and Transfusion Medicine, Department of Laboratory Medicine, Lund UniversityAbstract 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.https://doi.org/10.15252/emmm.201606660cancerribosomal gene haploinsufficiencyribosome function |
| spellingShingle | Ram Ajore David Raiser Marie McConkey Magnus Jöud Bernd Boidol Brenton Mar Gordon Saksena David M Weinstock Scott Armstrong Steven R Ellis Benjamin L Ebert Björn Nilsson Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations EMBO Molecular Medicine cancer ribosomal gene haploinsufficiency ribosome function |
| title | Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations |
| title_full | Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations |
| title_fullStr | Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations |
| title_full_unstemmed | Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations |
| title_short | Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations |
| title_sort | deletion of ribosomal protein genes is a common vulnerability in human cancer especially in concert with tp53 mutations |
| topic | cancer ribosomal gene haploinsufficiency ribosome function |
| url | https://doi.org/10.15252/emmm.201606660 |
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