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%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2014
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| Online Access: | http://hdl.handle.net/1721.1/84663 |
| _version_ | 1811072070785695744 |
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| author | Lander, Eric Steven |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Lander, Eric Steven |
| author_sort | Lander, Eric Steven |
| collection | MIT |
| 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%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (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 Mb (0.48 nonsilent) and notably 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%, and an additional 7.1% had focal deletions), MYCN (1.7%, causing 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 that rely on frequently altered oncogenic drivers. |
| first_indexed | 2024-09-23T09:00:23Z |
| format | Article |
| id | mit-1721.1/84663 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:00:23Z |
| publishDate | 2014 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/846632022-09-26T09:45:49Z The genetic landscape of high-risk neuroblastoma Lander, Eric Steven Massachusetts Institute of Technology. Department of Biology Lander, Eric S. 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%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (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 Mb (0.48 nonsilent) and notably 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%, and an additional 7.1% had focal deletions), MYCN (1.7%, causing 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 that rely on frequently altered oncogenic drivers. National Human Genome Research Institute (U.S.) (Grant U54HG003067) National Cancer Institute (U.S.) (Contract HHSN261200800001E) 2014-02-07T13:40:38Z 2014-02-07T13:40:38Z 2013-01 2012-09 Article http://purl.org/eprint/type/JournalArticle 1061-4036 1546-1718 http://hdl.handle.net/1721.1/84663 Pugh, Trevor J, Olena Morozova, Edward F Attiyeh, Shahab Asgharzadeh, Jun S Wei, Daniel Auclair, Scott L Carter, et al. “The genetic landscape of high-risk neuroblastoma.” Nature Genetics 45, no. 3 (January 20, 2013): 279-284. en_US http://dx.doi.org/10.1038/ng.2529 Nature Genetics Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | Lander, Eric Steven 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 |
| url | http://hdl.handle.net/1721.1/84663 |
| work_keys_str_mv | AT landerericsteven thegeneticlandscapeofhighriskneuroblastoma AT landerericsteven geneticlandscapeofhighriskneuroblastoma |