title: Chromosome 6p22 locus associated with clinically aggressive neuroblastoma.
abstract: BACKGROUND
  Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known.
  
  
  METHODS
  We performed a genomewide association study by first genotyping blood DNA samples from 1032 patients with neuroblastoma and 2043 control subjects of European descent using the Illumina HumanHap550 BeadChip. Samples from three independent groups of patients with neuroblastoma (a total of 720 patients) and 2128 control subjects were then genotyped to replicate significant associations.
  
  
  RESULTS
  We observed a significant association between neuroblastoma and the common minor alleles of three consecutive single-nucleotide polymorphisms (SNPs) at chromosome band 6p22 and containing the predicted genes FLJ22536 and FLJ44180 (P=1.71x10(-9) to 7.01x10(-10); allelic odds ratio, 1.39 to 1.40). Homozygosity for the at-risk G allele of the most significantly associated SNP, rs6939340, resulted in an increased likelihood of the development of neuroblastoma (odds ratio, 1.97; 95% confidence interval, 1.58 to 2.45). Subsequent genotyping of the three 6p22 SNPs in three independent case series confirmed our observation of an association (P=9.33x10(-15) at rs6939340 for joint analysis). Patients with neuroblastoma who were homozygous for the risk alleles at 6p22 were more likely to have metastatic (stage 4) disease (P=0.02), amplification of the MYCN oncogene in the tumor cells (P=0.006), and disease relapse (P=0.01).
  
  
  CONCLUSIONS
  A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma.
authors.affiliation: Division of Oncology and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA. maris@chop.edu
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Yael P
authors.initials: YP
authors.lastname: Mosse
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.forename: Stefano
authors.initials: S
authors.lastname: Monni
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scott
authors.forename: Shahab
authors.initials: S
authors.lastname: Asgharzadeh
authors.forename: Edward F
authors.initials: EF
authors.lastname: Attiyeh
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Diskin
authors.forename: Marci
authors.initials: M
authors.lastname: Laudenslager
authors.forename: Cynthia
authors.initials: C
authors.lastname: Winter
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Cole
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kim
authors.forename: Edward C
authors.initials: EC
authors.lastname: Frackelton
authors.forename: Tracy
authors.initials: T
authors.lastname: Casalunovo
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Eckert
authors.forename: Mario
authors.initials: M
authors.lastname: Capasso
authors.forename: Eric F
authors.initials: EF
authors.lastname: Rappaport
authors.forename: Carmel
authors.initials: C
authors.lastname: McConville
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: Robert C
authors.initials: RC
authors.lastname: Seeger
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.forename: Hongzhe
authors.initials: H
authors.lastname: Li
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins