You are here

Nat Genet DOI:10.1038/ng.2529

The genetic landscape of high-risk neuroblastoma.

Publication TypeJournal Article
Year of Publication2013
AuthorsPugh, TJ, Morozova, O, Attiyeh, EF, Asgharzadeh, S, Wei, JS, Auclair, D, Carter, SL, Cibulskis, K, Hanna, M, Kiezun, A, Kim, J, Lawrence, MS, Lichenstein, L, McKenna, A, Pedamallu, CSekhar, Ramos, AH, Shefler, E, Sivachenko, A, Sougnez, C, Stewart, C, Ally, A, Birol, I, Chiu, R, Corbett, RD, Hirst, M, Jackman, SD, Kamoh, B, Khodabakshi, AHadj, Krzywinski, M, Lo, A, Moore, RA, Mungall, KL, Qian, J, Tam, A, Thiessen, N, Zhao, Y, Cole, KA, Diamond, M, Diskin, SJ, Mosse, YP, Wood, AC, Ji, L, Sposto, R, Badgett, T, London, WB, Moyer, Y, Gastier-Foster, JM, Smith, MA, Auvil, JMGuidry, Gerhard, DS, Hogarty, MD, Jones, SJM, Lander, ES, Gabriel, SB, Getz, G, Seeger, RC, Khan, J, Marra, MA, Meyerson, M, Maris, JM
JournalNat Genet
Volume45
Issue3
Pages279-84
Date Published2013 Mar
ISSN1546-1718
KeywordsCell Line, Tumor, Exome, Genetic Predisposition to Disease, Genome, Human, Humans, Mutation, Neuroblastoma, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Transcriptome
Abstract

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.

URLhttp://dx.doi.org/10.1038/ng.2529
DOI10.1038/ng.2529
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23334666?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID23334666
PubMed Central IDPMC3682833
Grant ListCA124709 / CA / NCI NIH HHS / United States
CA98543 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
U54 HG002045 / HG / NHGRI NIH HHS / United States
R01 CA124709 / CA / NCI NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
RC1 MD004418 / MD / NIMHD NIH HHS / United States
U10 CA098413 / CA / NCI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
CA060104 / CA / NCI NIH HHS / United States
RC1MD004418 / MD / NIMHD NIH HHS / United States
HHSN261200800001E / / PHS HHS / United States
P30 CA016520 / CA / NCI NIH HHS / United States
U10 CA098543 / CA / NCI NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States
CA98413 / CA / NCI NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
R01 CA060104 / CA / NCI NIH HHS / United States