Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability
Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
eLife Sciences Publications, Ltd.
2017
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| Online Access: | http://hdl.handle.net/1721.1/109875 https://orcid.org/0000-0003-3159-8175 https://orcid.org/0000-0001-5367-2546 |
| _version_ | 1826200221459152896 |
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| author | Paolella, Brenton R Urbanski, Laura M Alberta, John A Bandopadhayay, Pratiti Nichols, Caitlin A Agarwalla, Pankaj K Brown, Meredith S Lamothe, Rebecca Yu, Yong Choi, Peter S Obeng, Esther A Heckl, Dirk Vazquez, Francisca Buhrlage, Sara J Stiles, Charles D Reed, Robin Gibson, William J Zack, Travis Ian Wei, Guo Wang, Belinda Tsherniak, Aviad Weir, Barbara A Root, David Cowley, Glenn S Ebert, Benjamin L Hahn, William Beroukhim, Rameen |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Paolella, Brenton R Urbanski, Laura M Alberta, John A Bandopadhayay, Pratiti Nichols, Caitlin A Agarwalla, Pankaj K Brown, Meredith S Lamothe, Rebecca Yu, Yong Choi, Peter S Obeng, Esther A Heckl, Dirk Vazquez, Francisca Buhrlage, Sara J Stiles, Charles D Reed, Robin Gibson, William J Zack, Travis Ian Wei, Guo Wang, Belinda Tsherniak, Aviad Weir, Barbara A Root, David Cowley, Glenn S Ebert, Benjamin L Hahn, William Beroukhim, Rameen |
| author_sort | Paolella, Brenton R |
| collection | MIT |
| description | Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency. |
| first_indexed | 2024-09-23T11:33:05Z |
| format | Article |
| id | mit-1721.1/109875 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:33:05Z |
| publishDate | 2017 |
| publisher | eLife Sciences Publications, Ltd. |
| record_format | dspace |
| spelling | mit-1721.1/1098752022-09-27T20:18:12Z Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability Paolella, Brenton R Urbanski, Laura M Alberta, John A Bandopadhayay, Pratiti Nichols, Caitlin A Agarwalla, Pankaj K Brown, Meredith S Lamothe, Rebecca Yu, Yong Choi, Peter S Obeng, Esther A Heckl, Dirk Vazquez, Francisca Buhrlage, Sara J Stiles, Charles D Reed, Robin Gibson, William J Zack, Travis Ian Wei, Guo Wang, Belinda Tsherniak, Aviad Weir, Barbara A Root, David Cowley, Glenn S Ebert, Benjamin L Hahn, William Beroukhim, Rameen Broad Institute of MIT and Harvard Gibson, William J Zack, Travis Ian Wei, Guo Wang, Belinda Tsherniak, Aviad Weir, Barbara A Root, David Cowley, Glenn S Ebert, Benjamin L Hahn, William Beroukhim, Rameen Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency. National Cancer Institute (U.S.) (R01 CA188228) National Cancer Institute (U.S.) (U01 CA176058) National Cancer Institute (U.S.) (F30 CA192725) 2017-06-14T20:35:20Z 2017-06-14T20:35:20Z 2017-02 2016-11 Article http://purl.org/eprint/type/JournalArticle 2050-084X http://hdl.handle.net/1721.1/109875 Paolella, Brenton R; Gibson, William J; Urbanski, Laura M; Alberta, John A; Zack, Travis I; Bandopadhayay, Pratiti; Nichols, Caitlin A et al. “Copy-Number and Gene Dependency Analysis Reveals Partial Copy Loss of Wild-Type SF3B1 as a Novel Cancer Vulnerability.” eLife 6 (February 2017): e23268 © 2017 Paolella et al https://orcid.org/0000-0003-3159-8175 https://orcid.org/0000-0001-5367-2546 en_US http://dx.doi.org/10.7554/eLife.23268 eLife Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf eLife Sciences Publications, Ltd. eLife |
| spellingShingle | Paolella, Brenton R Urbanski, Laura M Alberta, John A Bandopadhayay, Pratiti Nichols, Caitlin A Agarwalla, Pankaj K Brown, Meredith S Lamothe, Rebecca Yu, Yong Choi, Peter S Obeng, Esther A Heckl, Dirk Vazquez, Francisca Buhrlage, Sara J Stiles, Charles D Reed, Robin Gibson, William J Zack, Travis Ian Wei, Guo Wang, Belinda Tsherniak, Aviad Weir, Barbara A Root, David Cowley, Glenn S Ebert, Benjamin L Hahn, William Beroukhim, Rameen Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability |
| title | Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability |
| title_full | Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability |
| title_fullStr | Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability |
| title_full_unstemmed | Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability |
| title_short | Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability |
| title_sort | copy number and gene dependency analysis reveals partial copy loss of wild type sf3b1 as a novel cancer vulnerability |
| url | http://hdl.handle.net/1721.1/109875 https://orcid.org/0000-0003-3159-8175 https://orcid.org/0000-0001-5367-2546 |
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