title: The genetic landscape of high-risk neuroblastoma.
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.
authors: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Trevor J
authors: TJ
authors: Pugh
authors: Olena
authors: O
authors: Morozova
authors: Edward F
authors: EF
authors: Attiyeh
authors: Shahab
authors: S
authors: Asgharzadeh
authors: Jun S
authors: JS
authors: Wei
authors: Daniel
authors: D
authors: Auclair
authors: Scott L
authors: SL
authors: Carter
authors: Kristian
authors: K
authors: Cibulskis
authors: Megan
authors: M
authors: Hanna
authors: Adam
authors: A
authors: Kiezun
authors: Jaegil
authors: J
authors: Kim
authors: Michael S
authors: MS
authors: Lawrence
authors: Lee
authors: L
authors: Lichenstein
authors: Aaron
authors: A
authors: McKenna
authors: Chandra Sekhar
authors: CS
authors: Pedamallu
authors: Alex H
authors: AH
authors: Ramos
authors: Erica
authors: E
authors: Shefler
authors: Andrey
authors: A
authors: Sivachenko
authors: Carrie
authors: C
authors: Sougnez
authors: Chip
authors: C
authors: Stewart
authors: Adrian
authors: A
authors: Ally
authors: Inanc
authors: I
authors: Birol
authors: Readman
authors: R
authors: Chiu
authors: Richard D
authors: RD
authors: Corbett
authors: Martin
authors: M
authors: Hirst
authors: Shaun D
authors: SD
authors: Jackman
authors: Baljit
authors: B
authors: Kamoh
authors: Alireza Hadj
authors: AH
authors: Khodabakshi
authors: Martin
authors: M
authors: Krzywinski
authors: Allan
authors: A
authors: Lo
authors: Richard A
authors: RA
authors: Moore
authors: Karen L
authors: KL
authors: Mungall
authors: Jenny
authors: J
authors: Qian
authors: Angela
authors: A
authors: Tam
authors: Nina
authors: N
authors: Thiessen
authors: Yongjun
authors: Y
authors: Zhao
authors: Kristina A
authors: KA
authors: Cole
authors: Maura
authors: M
authors: Diamond
authors: Sharon J
authors: SJ
authors: Diskin
authors: Yael P
authors: YP
authors: Mosse
authors: Andrew C
authors: AC
authors: Wood
authors: Lingyun
authors: L
authors: Ji
authors: Richard
authors: R
authors: Sposto
authors: Thomas
authors: T
authors: Badgett
authors: Wendy B
authors: WB
authors: London
authors: Yvonne
authors: Y
authors: Moyer
authors: Julie M
authors: JM
authors: Gastier-Foster
authors: Malcolm A
authors: MA
authors: Smith
authors: Jaime M
authors: JM
authors: Guidry Auvil
authors: Daniela S
authors: DS
authors: Gerhard
authors: Michael D
authors: MD
authors: Hogarty
authors: Steven J M
authors: SJ
authors: Jones
authors: Eric S
authors: ES
authors: Lander
authors: Stacey B
authors: SB
authors: Gabriel
authors: Gad
authors: G
authors: Getz
authors: Robert C
authors: RC
authors: Seeger
authors: Javed
authors: J
authors: Khan
authors: Marco A
authors: MA
authors: Marra
authors: Matthew
authors: M
authors: Meyerson
authors: John M
authors: JM
authors: Maris
mesh_terms: D045744:Cell Line, Tumor; D059472:Exome; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D059467:Transcriptome