Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer
Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thu...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Cold Spring Harbor Laboratory Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483541/ https://www.ncbi.nlm.nih.gov/pubmed/23028188 http://dx.doi.org/10.1101/gr.137596.112 |
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author | Liang, Han Cheung, Lydia W.T. Li, Jie Ju, Zhenlin Yu, Shuangxing Stemke-Hale, Katherine Dogruluk, Turgut Lu, Yiling Liu, Xiuping Gu, Chao Guo, Wei Scherer, Steven E. Carter, Hannah Westin, Shannon N. Dyer, Mary D. Verhaak, Roeland G.W. Zhang, Fan Karchin, Rachel Liu, Chang-Gong Lu, Karen H. Broaddus, Russell R. Scott, Kenneth L. Hennessy, Bryan T. Mills, Gordon B. |
author_facet | Liang, Han Cheung, Lydia W.T. Li, Jie Ju, Zhenlin Yu, Shuangxing Stemke-Hale, Katherine Dogruluk, Turgut Lu, Yiling Liu, Xiuping Gu, Chao Guo, Wei Scherer, Steven E. Carter, Hannah Westin, Shannon N. Dyer, Mary D. Verhaak, Roeland G.W. Zhang, Fan Karchin, Rachel Liu, Chang-Gong Lu, Karen H. Broaddus, Russell R. Scott, Kenneth L. Hennessy, Bryan T. Mills, Gordon B. |
author_sort | Liang, Han |
collection | PubMed |
description | Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the “sensor” cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease. |
format | Online Article Text |
id | pubmed-3483541 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-34835412013-05-01 Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer Liang, Han Cheung, Lydia W.T. Li, Jie Ju, Zhenlin Yu, Shuangxing Stemke-Hale, Katherine Dogruluk, Turgut Lu, Yiling Liu, Xiuping Gu, Chao Guo, Wei Scherer, Steven E. Carter, Hannah Westin, Shannon N. Dyer, Mary D. Verhaak, Roeland G.W. Zhang, Fan Karchin, Rachel Liu, Chang-Gong Lu, Karen H. Broaddus, Russell R. Scott, Kenneth L. Hennessy, Bryan T. Mills, Gordon B. Genome Res Research Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the “sensor” cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease. Cold Spring Harbor Laboratory Press 2012-11 /pmc/articles/PMC3483541/ /pubmed/23028188 http://dx.doi.org/10.1101/gr.137596.112 Text en © 2012, Published by Cold Spring Harbor Laboratory Press This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/. |
spellingShingle | Research Liang, Han Cheung, Lydia W.T. Li, Jie Ju, Zhenlin Yu, Shuangxing Stemke-Hale, Katherine Dogruluk, Turgut Lu, Yiling Liu, Xiuping Gu, Chao Guo, Wei Scherer, Steven E. Carter, Hannah Westin, Shannon N. Dyer, Mary D. Verhaak, Roeland G.W. Zhang, Fan Karchin, Rachel Liu, Chang-Gong Lu, Karen H. Broaddus, Russell R. Scott, Kenneth L. Hennessy, Bryan T. Mills, Gordon B. Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer |
title | Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer |
title_full | Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer |
title_fullStr | Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer |
title_full_unstemmed | Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer |
title_short | Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer |
title_sort | whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483541/ https://www.ncbi.nlm.nih.gov/pubmed/23028188 http://dx.doi.org/10.1101/gr.137596.112 |
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