title: Association of age at diagnosis and genetic mutations in patients with neuroblastoma.
abstract: BACKGROUND
  Neuroblastoma is diagnosed over a wide age range from birth through young adulthood, and older age at diagnosis is associated with a decline in survivability.
  
  
  OBJECTIVE
  To identify genetic mutations that are associated with age at diagnosis in patients with metastatic neuroblastoma.
  
  
  METHODS
  Whole genome sequencing was performed on DNA from diagnostic tumors and their matched germlines from 40 patients with metastatic neuroblastoma obtained between 1987 and 2009. Age groups at diagnosis included infants (0-<18 months), children (18 months-<12 years), and adolescents and young adults (≥12 years). To confirm the findings from this discovery cohort, validation testing using tumors from an additional 64 patients obtained between 1985 and 2009 also was performed. Formalin-fixed, paraffin-embedded tumor tissue was used for immunohistochemistry and fluorescence in situ hybridization. Telomere lengths were analyzed using whole genome sequencing data, quantitative polymerase chain reaction, and fluorescent in situ hybridization.
  
  
  METHODS
  Somatic recurrent mutations in tumors from patients with neuroblastoma correlated with the age at diagnosis and telomere length.
  
  
  RESULTS
  In the discovery cohort (n = 40), mutations in the ATRX gene were identified in 100% (95% CI, 50%-100%) of tumors from patients in the adolescent and young adult group (5 of 5), in 17% (95% CI, 7%-36%) of tumors from children (5 of 29), and 0% (95% CI, 0%-40%) of tumors from infants (0 of 6). In the validation cohort (n = 64), mutations in the ATRX gene were identified in 33% (95% CI, 17%-54%) of tumors from patients in the adolescent and young adult group (9 of 27), in 16% (95% CI, 6%-35%) of tumors from children (4 of 25), and in 0% (95% CI, 0%-24%) of tumors from infants (0 of 12). In both cohorts (N = 104), mutations in the ATRX gene were identified in 44% (95% CI, 28%-62%) of tumors from patients in the adolescent and young adult group (14 of 32), in 17% (95% CI, 9%-29%) of tumors from children (9 of 54), and in 0% (95% CI, 0%-17%) of tumors from infants (0 of 18). ATRX mutations were associated with an absence of the ATRX protein in the nucleus and with long telomeres.
  
  
  CONCLUSIONS
  ATRX mutations were associated with age at diagnosis in children and young adults with stage 4 neuroblastoma.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00588068.
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Nai-Kong V
authors.initials: NK
authors.lastname: Cheung
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.forename: Matthew
authors.initials: M
authors.lastname: Parker
authors.forename: Armita
authors.initials: A
authors.lastname: Bahrami
authors.forename: Satish K
authors.initials: SK
authors.lastname: Tickoo
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Alberto S
authors.initials: AS
authors.lastname: Pappo
authors.forename: Sara
authors.initials: S
authors.lastname: Federico
authors.forename: James
authors.initials: J
authors.lastname: Dalton
authors.forename: Irene Y
authors.initials: IY
authors.lastname: Cheung
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Robert
authors.initials: R
authors.lastname: Fulton
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Jared
authors.initials: J
authors.lastname: Becksfort
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.forename: David
authors.initials: D
authors.lastname: Ellison
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004265:DNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D059505:Telomere Homeostasis; D000075924:X-linked Nuclear Protein; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein