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Deletion of ribosom...
Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations
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- Ajore, Ram (author)
- Lund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups
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- Raiser, David (author)
- Harvard Medical School
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- McConkey, Marie E. (author)
- Harvard Medical School
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- Jöud, Magnus (author)
- Lund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine
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- Boidol, Bernd (author)
- Harvard Medical School
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- Mar, Brenton G (author)
- Harvard Medical School
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- Saksena, Gordon (author)
- Broad Institute
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- Weinstock, David M (author)
- Dana-Farber Cancer Institute
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- Armstrong, Scott (author)
- Memorial Sloan-Kettering Cancer Center
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- Ellis, Steven R (author)
- University of Louisville
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- Ebert, Benjamin L. (author)
- Broad Institute
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- Nilsson, Björn (author)
- Lund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups,Broad Institute
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(creator_code:org_t)
- 2017-03-06
- 2017
- English 10 s.
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In: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 9:4, s. 498-507
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- cancer
- ribosomal gene haploinsufficiency
- ribosome function
- protein p53
- ribosome protein
- short hairpin RNA
- article
- cancer cell line
- cancer genetics
- cancer tissue
- cell growth
- cell line
- controlled study
- disease association
- gene deletion
- gene mutation
- gene silencing
- genetic screening
- haploinsufficiency
- hemizygote
- homozygote
- human
- human cell
- malignant neoplasm
- nonhuman
- ribosomal protein gene
- TP53 gene
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Ajore, Ram
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Raiser, David
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McConkey, Marie ...
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Jöud, Magnus
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Boidol, Bernd
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Mar, Brenton G
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show more...
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Saksena, Gordon
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Weinstock, David ...
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Armstrong, Scott
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Ellis, Steven R
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Ebert, Benjamin ...
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Nilsson, Björn
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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EMBO Molecular M ...
- By the university
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Lund University