|
|
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.
Source Information
From the Division of Oncology and the Center for Childhood Cancer Research (J.M.M., Y.P.M., C.H., E.F.A., S.J.D., M.L., C.W., K.A.C., E.F.R.), the Center for Applied Genomics ( J.P.B., J.T.G., C.K., E.C.F., T.C., A.W.E., S.F.A.G., H.H.), and the Division of Genetics (M.C., M.D., S.F.A.G., H.H.), Children's Hospital of Philadelphia; and the Department of Pediatrics (J.M.M., Y.P.M., C.H., E.F.A., S.J.D., M.L., C.W., K.A.C., E.F.R.), the Abramson Family Cancer Research Institute (J.M.M.), the Department of Biostatistics and Epidemiology (S.M., M.D., H.L.), and the Department of Pediatrics (M.C., M.D., S.F.A.G., H.H.), University of Pennsylvania School of Medicine — all in Philadelphia; the Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, United Kingdom (R.H.S., N.R.); the Division of Hematology–Oncology and the Saban Research Institute, Children's Hospital Los Angeles, and the Keck School of Medicine, University of Southern California — both in Los Angeles (S.A., R.C.S.); Federico II University, Centro di Ingegneria Genetica Biotecnologie Avanzate, Naples, Italy (M.C.); the Division of Reproductive and Child Health and CRUK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom (C.M.); the Department of Statistics, University of Florida, and the Children's Oncology Group — both in Gainesville (W.B.L.); and the Department of Experimental Medicine, La Sapienza University of Rome, Rome (M.D.).
Dr. Mosse and Mr. Bradfield contributed equally to this article.
This article (10.1056/NEJMoa0708698) was published at www.nejm.org on May 7, 2008.
Address reprint requests to Dr. Maris at the Children's Hospital of Philadelphia, 907A, 3516 Civic Center Blvd., Philadelphia, PA 19104-4318, or at maris{at}chop.edu, or to Dr. Hakonarson at the Children's Hospital of Philadelphia, ARC12, 3516 Civic Center Blvd., Philadelphia, PA 19104-4318, or at hakonarson{at}chop.edu.
This article has been cited by other articles:
HOME | SUBSCRIBE | SEARCH | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | PRIVACY | HELP | beta.nejm.org Comments and questions? Please contact us. The New England Journal of Medicine is owned, published, and copyrighted © 2009 Massachusetts Medical Society. All rights reserved. |
Previous
