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: John M Maris, Yael P Mosse, Jonathan P Bradfield, Cuiping Hou, Stefano Monni, Richard H Scott, Shahab Asgharzadeh, Edward F Attiyeh, Sharon J Diskin, Marci Laudenslager, Cynthia Winter, Kristina A Cole, Joseph T Glessner, Cecilia Kim, Edward C Frackelton, Tracy Casalunovo, Andrew W Eckert, Mario Capasso, Eric F Rappaport, Carmel McConville, Wendy B London, Robert C Seeger, Nazneen Rahman, Marcella Devoto, Struan F A Grant, Hongzhe Li, Hakon Hakonarson
• Journal: The New England journal of medicine (N Engl J Med) Vol. 358 Issue 24 Pg. 2585-93 (Jun 12 2008) ISSN: 1533-4406 [Electronic] United States
• PMID: 18463370 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: 2008 Massachusetts Medical Society

Chemical References

• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• Nuclear Proteins
• Oncogene Proteins

Topics

• Alleles
• Case-Control Studies
• Cell Transformation, Neoplastic (genetics)
• Child, Preschool
• Chromosomes, Human, Pair 6 (genetics)
• Disease-Free Survival
• Female
• Genetic Predisposition to Disease
• Genotype
• Homozygote
• Humans
• Infant
• Male
• N-Myc Proto-Oncogene Protein
• Neoplasm Staging
• Neuroblastoma (genetics, pathology)
• Nuclear Proteins (genetics)
• Oncogene Proteins (genetics)
• Polymorphism, Single Nucleotide