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Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer
The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181647/ https://www.ncbi.nlm.nih.gov/pubmed/32332753 http://dx.doi.org/10.1038/s41467-020-15951-0 |
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author | Corona, Rosario I. Seo, Ji-Heui Lin, Xianzhi Hazelett, Dennis J. Reddy, Jessica Fonseca, Marcos A. S. Abassi, Forough Lin, Yvonne G. Mhawech-Fauceglia, Paulette Y. Shah, Sohrab P. Huntsman, David G. Gusev, Alexander Karlan, Beth Y. Berman, Benjamin P. Freedman, Matthew L. Gayther, Simon A. Lawrenson, Kate |
author_facet | Corona, Rosario I. Seo, Ji-Heui Lin, Xianzhi Hazelett, Dennis J. Reddy, Jessica Fonseca, Marcos A. S. Abassi, Forough Lin, Yvonne G. Mhawech-Fauceglia, Paulette Y. Shah, Sohrab P. Huntsman, David G. Gusev, Alexander Karlan, Beth Y. Berman, Benjamin P. Freedman, Matthew L. Gayther, Simon A. Lawrenson, Kate |
author_sort | Corona, Rosario I. |
collection | PubMed |
description | The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and then integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4) and ZSCAN12 (P = 0.02). CRISPR/Cas9 knockout of this enhancer induces downregulation of both genes. Globally, there is an enrichment of single nucleotide variants in active binding sites for TEAD4 (P = 6 × 10-11) and its binding partner PAX8 (P = 2×10-10), a known lineage-specific transcription factor in OC. In addition, the collection of cis REs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during OC development. |
format | Online Article Text |
id | pubmed-7181647 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-71816472020-04-29 Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer Corona, Rosario I. Seo, Ji-Heui Lin, Xianzhi Hazelett, Dennis J. Reddy, Jessica Fonseca, Marcos A. S. Abassi, Forough Lin, Yvonne G. Mhawech-Fauceglia, Paulette Y. Shah, Sohrab P. Huntsman, David G. Gusev, Alexander Karlan, Beth Y. Berman, Benjamin P. Freedman, Matthew L. Gayther, Simon A. Lawrenson, Kate Nat Commun Article The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and then integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4) and ZSCAN12 (P = 0.02). CRISPR/Cas9 knockout of this enhancer induces downregulation of both genes. Globally, there is an enrichment of single nucleotide variants in active binding sites for TEAD4 (P = 6 × 10-11) and its binding partner PAX8 (P = 2×10-10), a known lineage-specific transcription factor in OC. In addition, the collection of cis REs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during OC development. Nature Publishing Group UK 2020-04-24 /pmc/articles/PMC7181647/ /pubmed/32332753 http://dx.doi.org/10.1038/s41467-020-15951-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Corona, Rosario I. Seo, Ji-Heui Lin, Xianzhi Hazelett, Dennis J. Reddy, Jessica Fonseca, Marcos A. S. Abassi, Forough Lin, Yvonne G. Mhawech-Fauceglia, Paulette Y. Shah, Sohrab P. Huntsman, David G. Gusev, Alexander Karlan, Beth Y. Berman, Benjamin P. Freedman, Matthew L. Gayther, Simon A. Lawrenson, Kate Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer |
title | Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer |
title_full | Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer |
title_fullStr | Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer |
title_full_unstemmed | Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer |
title_short | Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer |
title_sort | non-coding somatic mutations converge on the pax8 pathway in ovarian cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181647/ https://www.ncbi.nlm.nih.gov/pubmed/32332753 http://dx.doi.org/10.1038/s41467-020-15951-0 |
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