Chromosome 6p22 Locus Associated with Clinically Aggressive Neuroblastoma
Somatic characteristics of neuroblastoma tumors — such as MYCN amplification — are associated with more aggressive disease. This report shows that persons who inherit variants on chromosome 6p22 are more susceptible to the development of the disease than those who do not inherit these variants. This...
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| Published in | The New England journal of medicine Vol. 358; no. 24; pp. 2585 - 2593 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Boston, MA
Massachusetts Medical Society
12.06.2008
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Somatic characteristics of neuroblastoma tumors — such as
MYCN
amplification — are associated with more aggressive disease. This report shows that persons who inherit variants on chromosome 6p22 are more susceptible to the development of the disease than those who do not inherit these variants.
This report shows that persons who inherit variants on chromosome 6p22 are more susceptible to the development of neuroblastoma than those who do not inherit these variants.
Despite marked improvements in the cure rates for many childhood cancers, neuroblastoma remains an important clinical problem, accounting for 15% of the deaths attributable to malignant conditions in children.
1
It is the most common solid cancer of early childhood, and approximately half of all patients with neuroblastoma present with widely disseminated disease that is often refractory to intensive chemoradiotherapy. Cure rates among these high-risk patients remain less than 40%, despite dramatic increases in the intensity of chemoradiotherapy, and survivors often have serious lifelong coexisting conditions.
2
–
4
Somatically acquired genomic aberrations in neuroblastoma are of fundamental importance for predicting the tumor . . . |
|---|---|
| AbstractList | 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.BACKGROUNDNeuroblastoma 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.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.METHODSWe 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.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).RESULTSWe 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).A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma.CONCLUSIONSA common genetic variation at chromosome band 6p22 is associated with susceptibility to 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=1.71×10-9 to 7.01×10-10 ; 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=9.33×10-15 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. 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. 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. 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). A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma. Somatic characteristics of neuroblastoma tumors — such as MYCN amplification — are associated with more aggressive disease. This report shows that persons who inherit variants on chromosome 6p22 are more susceptible to the development of the disease than those who do not inherit these variants. This report shows that persons who inherit variants on chromosome 6p22 are more susceptible to the development of neuroblastoma than those who do not inherit these variants. Despite marked improvements in the cure rates for many childhood cancers, neuroblastoma remains an important clinical problem, accounting for 15% of the deaths attributable to malignant conditions in children. 1 It is the most common solid cancer of early childhood, and approximately half of all patients with neuroblastoma present with widely disseminated disease that is often refractory to intensive chemoradiotherapy. Cure rates among these high-risk patients remain less than 40%, despite dramatic increases in the intensity of chemoradiotherapy, and survivors often have serious lifelong coexisting conditions. 2 – 4 Somatically acquired genomic aberrations in neuroblastoma are of fundamental importance for predicting the tumor . . . |
| Author | Winter, Cynthia Maris, John M Casalunovo, Tracy Rappaport, Eric F Hakonarson, Hakon Scott, Richard H Cole, Kristina A Seeger, Robert C Devoto, Marcella Hou, Cuiping Attiyeh, Edward F Bradfield, Jonathan P Kim, Cecilia Laudenslager, Marci Asgharzadeh, Shahab Glessner, Joseph T Frackelton, Edward C Grant, Struan F.A Li, Hongzhe Capasso, Mario Rahman, Nazneen Monni, Stefano Diskin, Sharon J McConville, Carmel Mosse, Yael P Eckert, Andrew W London, Wendy B |
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| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20416479$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/18463370$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | Copyright © 2008 Massachusetts Medical Society. All rights reserved. 2008 INIST-CNRS 2008 Massachusetts Medical Society |
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| Snippet | Somatic characteristics of neuroblastoma tumors — such as
MYCN
amplification — are associated with more aggressive disease. This report shows that persons who... Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is... Background Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal.... |
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| SubjectTerms | Alleles Biological and medical sciences Case-Control Studies Cell Transformation, Neoplastic - genetics Child, Preschool Children & youth Chromosomes, Human, Pair 6 - genetics Disease-Free Survival Female General aspects Genetic Predisposition to Disease Genetic testing Genotype Health care networks Homozygote Humans Infant Male Medical sciences N-Myc Proto-Oncogene Protein Neoplasm Staging Neuroblastoma - genetics Neuroblastoma - pathology Neurology Nuclear Proteins - genetics Oncogene Proteins - genetics Polymorphism, Single Nucleotide Tumors Tumors of the nervous system. Phacomatoses |
| Title | Chromosome 6p22 Locus Associated with Clinically Aggressive Neuroblastoma |
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