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The genetic landscape of high-risk neuroblastoma
Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%(1). To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of wh...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682833/ https://www.ncbi.nlm.nih.gov/pubmed/23334666 http://dx.doi.org/10.1038/ng.2529 |
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author | Pugh, Trevor J. Morozova, Olena Attiyeh, Edward F. Asgharzadeh, Shahab Wei, Jun S. Auclair, Daniel Carter, Scott L. Cibulskis, Kristian Hanna, Megan Kiezun, Adam Kim, Jaegil Lawrence, Michael S. Lichenstein, Lee McKenna, Aaron Pedamallu, Chandra Sekhar Ramos, Alex H. Shefler, Erica Sivachenko, Andrey Sougnez, Carrie Stewart, Chip Ally, Adrian Birol, Inanc Chiu, Readman Corbett, Richard D. Hirst, Martin Jackman, Shaun D. Kamoh, Baljit Khodabakshi, Alireza Hadj Krzywinski, Martin Lo, Allan Moore, Richard A. Mungall, Karen L. Qian, Jenny Tam, Angela Thiessen, Nina Zhao, Yongjun Cole, Kristina A. Diamond, Maura Diskin, Sharon J. Mosse, Yael P. Wood, Andrew C. Ji, Lingyun Sposto, Richard Badgett, Thomas London, Wendy B. Moyer, Yvonne Gastier-Foster, Julie M. Smith, Malcolm A. Auvil, Jaime M. Guidry Gerhard, Daniela S. Hogarty, Michael D. Jones, Steven J. M. Lander, Eric S. Gabriel, Stacey B. Getz, Gad Seeger, Robert C. Khan, Javed Marra, Marco A. Meyerson, Matthew Maris, John M. |
author_facet | Pugh, Trevor J. Morozova, Olena Attiyeh, Edward F. Asgharzadeh, Shahab Wei, Jun S. Auclair, Daniel Carter, Scott L. Cibulskis, Kristian Hanna, Megan Kiezun, Adam Kim, Jaegil Lawrence, Michael S. Lichenstein, Lee McKenna, Aaron Pedamallu, Chandra Sekhar Ramos, Alex H. Shefler, Erica Sivachenko, Andrey Sougnez, Carrie Stewart, Chip Ally, Adrian Birol, Inanc Chiu, Readman Corbett, Richard D. Hirst, Martin Jackman, Shaun D. Kamoh, Baljit Khodabakshi, Alireza Hadj Krzywinski, Martin Lo, Allan Moore, Richard A. Mungall, Karen L. Qian, Jenny Tam, Angela Thiessen, Nina Zhao, Yongjun Cole, Kristina A. Diamond, Maura Diskin, Sharon J. Mosse, Yael P. Wood, Andrew C. Ji, Lingyun Sposto, Richard Badgett, Thomas London, Wendy B. Moyer, Yvonne Gastier-Foster, Julie M. Smith, Malcolm A. Auvil, Jaime M. Guidry Gerhard, Daniela S. Hogarty, Michael D. Jones, Steven J. M. Lander, Eric S. Gabriel, Stacey B. Getz, Gad Seeger, Robert C. Khan, Javed Marra, Marco A. Meyerson, Matthew Maris, John M. |
author_sort | Pugh, Trevor J. |
collection | PubMed |
description | Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%(1). To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of whole exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per megabase (0.48 non-silent), and remarkably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, an additional 7.1% had focal deletions), MYCN (1.7%, a recurrent p.Pro44Leu alteration), and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1, and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies reliant upon frequently altered oncogenic drivers. |
format | Online Article Text |
id | pubmed-3682833 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-36828332013-09-01 The genetic landscape of high-risk neuroblastoma Pugh, Trevor J. Morozova, Olena Attiyeh, Edward F. Asgharzadeh, Shahab Wei, Jun S. Auclair, Daniel Carter, Scott L. Cibulskis, Kristian Hanna, Megan Kiezun, Adam Kim, Jaegil Lawrence, Michael S. Lichenstein, Lee McKenna, Aaron Pedamallu, Chandra Sekhar Ramos, Alex H. Shefler, Erica Sivachenko, Andrey Sougnez, Carrie Stewart, Chip Ally, Adrian Birol, Inanc Chiu, Readman Corbett, Richard D. Hirst, Martin Jackman, Shaun D. Kamoh, Baljit Khodabakshi, Alireza Hadj Krzywinski, Martin Lo, Allan Moore, Richard A. Mungall, Karen L. Qian, Jenny Tam, Angela Thiessen, Nina Zhao, Yongjun Cole, Kristina A. Diamond, Maura Diskin, Sharon J. Mosse, Yael P. Wood, Andrew C. Ji, Lingyun Sposto, Richard Badgett, Thomas London, Wendy B. Moyer, Yvonne Gastier-Foster, Julie M. Smith, Malcolm A. Auvil, Jaime M. Guidry Gerhard, Daniela S. Hogarty, Michael D. Jones, Steven J. M. Lander, Eric S. Gabriel, Stacey B. Getz, Gad Seeger, Robert C. Khan, Javed Marra, Marco A. Meyerson, Matthew Maris, John M. Nat Genet Article Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%(1). To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of whole exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per megabase (0.48 non-silent), and remarkably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, an additional 7.1% had focal deletions), MYCN (1.7%, a recurrent p.Pro44Leu alteration), and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1, and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies reliant upon frequently altered oncogenic drivers. 2013-01-20 2013-03 /pmc/articles/PMC3682833/ /pubmed/23334666 http://dx.doi.org/10.1038/ng.2529 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Pugh, Trevor J. Morozova, Olena Attiyeh, Edward F. Asgharzadeh, Shahab Wei, Jun S. Auclair, Daniel Carter, Scott L. Cibulskis, Kristian Hanna, Megan Kiezun, Adam Kim, Jaegil Lawrence, Michael S. Lichenstein, Lee McKenna, Aaron Pedamallu, Chandra Sekhar Ramos, Alex H. Shefler, Erica Sivachenko, Andrey Sougnez, Carrie Stewart, Chip Ally, Adrian Birol, Inanc Chiu, Readman Corbett, Richard D. Hirst, Martin Jackman, Shaun D. Kamoh, Baljit Khodabakshi, Alireza Hadj Krzywinski, Martin Lo, Allan Moore, Richard A. Mungall, Karen L. Qian, Jenny Tam, Angela Thiessen, Nina Zhao, Yongjun Cole, Kristina A. Diamond, Maura Diskin, Sharon J. Mosse, Yael P. Wood, Andrew C. Ji, Lingyun Sposto, Richard Badgett, Thomas London, Wendy B. Moyer, Yvonne Gastier-Foster, Julie M. Smith, Malcolm A. Auvil, Jaime M. Guidry Gerhard, Daniela S. Hogarty, Michael D. Jones, Steven J. M. Lander, Eric S. Gabriel, Stacey B. Getz, Gad Seeger, Robert C. Khan, Javed Marra, Marco A. Meyerson, Matthew Maris, John M. The genetic landscape of high-risk neuroblastoma |
title | The genetic landscape of high-risk neuroblastoma |
title_full | The genetic landscape of high-risk neuroblastoma |
title_fullStr | The genetic landscape of high-risk neuroblastoma |
title_full_unstemmed | The genetic landscape of high-risk neuroblastoma |
title_short | The genetic landscape of high-risk neuroblastoma |
title_sort | genetic landscape of high-risk neuroblastoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682833/ https://www.ncbi.nlm.nih.gov/pubmed/23334666 http://dx.doi.org/10.1038/ng.2529 |
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