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Title:
The genetic landscape of high-risk neuroblastoma | Nature Genetics
Description:
John Maris, Matthew Meyerson, Marco Marra and colleagues report results of a large-scale sequencing study of neuroblastoma. They observe a low median exonic mutation frequency and strikingly few recurrently mutated genes in these tumors, highlighting challenges for developing targeted therapeutic strategies based on frequently mutated oncogenic drivers. 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.
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headline:The genetic landscape of high-risk neuroblastoma
description:John Maris, Matthew Meyerson, Marco Marra and colleagues report results of a large-scale sequencing study of neuroblastoma. They observe a low median exonic mutation frequency and strikingly few recurrently mutated genes in these tumors, highlighting challenges for developing targeted therapeutic strategies based on frequently mutated oncogenic drivers. 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.
datePublished:2013-01-20T00:00:00Z
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headline:The genetic landscape of high-risk neuroblastoma
description:John Maris, Matthew Meyerson, Marco Marra and colleagues report results of a large-scale sequencing study of neuroblastoma. They observe a low median exonic mutation frequency and strikingly few recurrently mutated genes in these tumors, highlighting challenges for developing targeted therapeutic strategies based on frequently mutated oncogenic drivers. 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.
datePublished:2013-01-20T00:00:00Z
dateModified:2013-01-20T00:00:00Z
pageStart:279
pageEnd:284
sameAs:https://doi.org/10.1038/ng.2529
keywords:
Cancer genetics
CNS cancer
Mutation
Biomedicine
general
Human Genetics
Cancer Research
Agriculture
Gene Function
Animal Genetics and Genomics
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type:PostalAddress
type:Organization
name:Keck School of Medicine, University of Southern California
address:
name:Keck School of Medicine, University of Southern California, Los Angeles, USA
type:PostalAddress
type:Organization
name:Javed Khan
affiliation:
name:Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, National Institutes of Health
address:
name:Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, National Institutes of Health, Gaithersburg, USA
type:PostalAddress
type:Organization
name:Marco A Marra
affiliation:
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia
address:
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
type:PostalAddress
type:Organization
name:University of British Columbia
address:
name:Department of Medical Genetics, University of British Columbia, Vancouver, Canada
type:PostalAddress
type:Organization
email:[email protected]
name:Matthew Meyerson
affiliation:
name:The Broad Institute of MIT and Harvard
address:
name:The Broad Institute of MIT and Harvard, Cambridge, USA
type:PostalAddress
type:Organization
name:Harvard Medical School
address:
name:Harvard Medical School, Boston, USA
type:PostalAddress
type:Organization
name:Dana-Farber Cancer Institute
address:
name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
type:PostalAddress
type:Organization
email:[email protected]
name:John M Maris
affiliation:
name:The Children's Hospital of Philadelphia
address:
name:Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
type:PostalAddress
type:Organization
name:Center for Childhood Cancer Research, The Children's Hospital of Philadelphia
address:
name:Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, USA
type:PostalAddress
type:Organization
name:Perelman School of Medicine at the University of Pennsylvania
address:
name:Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
type:PostalAddress
type:Organization
name:Abramson Family Cancer Research Institute
address:
name:Abramson Family Cancer Research Institute, Philadelphia, USA
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:Harvard Medical School, Boston, USA
name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Department of Medical Genetics, University of British Columbia, Vancouver, Canada
name:Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
name:Division of Hematology/Oncology, The Children's Hospital Los Angeles, Los Angeles, USA
name:Saban Research Institute, The Children's Hospital Los Angeles, Los Angeles, USA
name:Keck School of Medicine, University of Southern California, Los Angeles, USA
name:Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, National Institutes of Health, Gaithersburg, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
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name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:Harvard Medical School, Boston, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
name:Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
name:Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
name:Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
name:Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
name:Division of Hematology/Oncology, The Children's Hospital Los Angeles, Los Angeles, USA
name:Saban Research Institute, The Children's Hospital Los Angeles, Los Angeles, USA
name:Keck School of Medicine, University of Southern California, Los Angeles, USA
name:Division of Hematology/Oncology, The Children's Hospital Los Angeles, Los Angeles, USA
name:Saban Research Institute, The Children's Hospital Los Angeles, Los Angeles, USA
name:Keck School of Medicine, University of Southern California, Los Angeles, USA
name:Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, National Institutes of Health, Gaithersburg, USA
name:Harvard Medical School, Boston, USA
name:Children's Hospital Boston/Dana-Farber Cancer Institute and Children's Oncology Group, Boston, USA
name:Biopathology Center, Nationwide Children's Hospital, Columbus, USA
name:The Ohio State University College of Medicine, Columbus, USA
name:Biopathology Center, Nationwide Children's Hospital, Columbus, USA
name:The Ohio State University College of Medicine, Columbus, USA
name:Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, USA
name:Office of Cancer Genomics, National Cancer Institute, Bethesda, USA
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name:Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:Division of Hematology/Oncology, The Children's Hospital Los Angeles, Los Angeles, USA
name:Saban Research Institute, The Children's Hospital Los Angeles, Los Angeles, USA
name:Keck School of Medicine, University of Southern California, Los Angeles, USA
name:Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, National Institutes of Health, Gaithersburg, USA
name:Genome Sciences Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
name:Department of Medical Genetics, University of British Columbia, Vancouver, Canada
name:The Broad Institute of MIT and Harvard, Cambridge, USA
name:Harvard Medical School, Boston, USA
name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
name:Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, USA
name:Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
name:Abramson Family Cancer Research Institute, Philadelphia, USA
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