Chromosome 6p22 locus associated with clinically aggressive neuroblastoma.
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.
Maris
John M
JM
Division of Oncology and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA. maris@chop.edu
Mosse
Yael P
YP
Bradfield
Jonathan P
JP
Hou
Cuiping
C
Monni
Stefano
S
Scott
Richard H
RH
Asgharzadeh
Shahab
S
Attiyeh
Edward F
EF
Diskin
Sharon J
SJ
Laudenslager
Marci
M
Winter
Cynthia
C
Cole
Kristina A
KA
Glessner
Joseph T
JT
Kim
Cecilia
C
Frackelton
Edward C
EC
Casalunovo
Tracy
T
Eckert
Andrew W
AW
Capasso
Mario
M
Rappaport
Eric F
EF
McConville
Carmel
C
London
Wendy B
WB
Seeger
Robert C
RC
Rahman
Nazneen
N
Devoto
Marcella
M
Grant
Struan F A
SF
Li
Hongzhe
H
Hakonarson
Hakon
H
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
C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins