{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"study_type":["Case-Control"],"host":["dbGaP"],"description":["EGA study phs000124.v2.p1"],"host_link":["http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000124.v2.p1"],"source":["dbGaP"],"repository":["EGA"],"category":["restricted"],"full_dataset_link":["https://ega-archive.org/studies/phs000124.v2.p1"],"pubmed_abstract":["Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths. To identify genetic risk factors for neuroblastoma, we performed a genome-wide association study (GWAS) on 2,251 patients and 6,097 control subjects of European ancestry from four case series. Here we report a significant association within LIM domain only 1 (LMO1) at 11p15.4 (rs110419, combined P = 5.2 × 10(-16), odds ratio of risk allele = 1.34 (95% confidence interval 1.25-1.44)). The signal was enriched in the subset of patients with the most aggressive form of the disease. LMO1 encodes a cysteine-rich transcriptional regulator, and its paralogues (LMO2, LMO3 and LMO4) have each been previously implicated in cancer. In parallel, we analysed genome-wide DNA copy number alterations in 701 primary tumours. We found that the LMO1 locus was aberrant in 12.4% through a duplication event, and that this event was associated with more advanced disease (P < 0.0001) and survival (P = 0.041). The germline single nucleotide polymorphism (SNP) risk alleles and somatic copy number gains were associated with increased LMO1 expression in neuroblastoma cell lines and primary tumours, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA (shRNA)-mediated depletion of LMO1 inhibited growth of neuroblastoma cells with high LMO1 expression, whereas forced expression of LMO1 in neuroblastoma cells with low LMO1 expression enhanced proliferation. These data show that common polymorphisms at the LMO1 locus are strongly associated with susceptibility to developing neuroblastoma, but also may influence the likelihood of further somatic alterations at this locus, leading to malignant progression.","Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in human cancer, we performed a genome-wide association study of CNVs in the childhood cancer neuroblastoma, a disease in which single nucleotide polymorphism variations are known to influence susceptibility. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at approximately 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. Here we describe the identification of a common CNV at chromosome 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets. This CNV was validated by quantitative polymerase chain reaction, fluorescent in situ hybridization and analysis of matched tumour specimens, and was shown to be heritable in an independent set of 713 cancer-free parent-offspring trios. We identified a previously unknown transcript within the CNV that showed high sequence similarity to several neuroblastoma breakpoint family (NBPF) genes and represents a new member of this gene family (NBPF23). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and the expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a previously unknown neuroblastoma breakpoint family gene in early tumorigenesis of this childhood cancer.","<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma.","We conducted a SNP-based genome-wide association study (GWAS) focused on the high-risk subset of neuroblastoma. As our previous unbiased GWAS showed strong association of common 6p22 SNP alleles with aggressive neuroblastoma, we restricted our analysis here to 397 high-risk cases compared to 2,043 controls. We detected new significant association of six SNPs at 2q35 within the BARD1 locus (P(allelic) = 2.35 x 10(-9)-2.25 x 10(-8)). We confirmed each SNP association in a second series of 189 high-risk cases and 1,178 controls (P(allelic) = 7.90 x 10(-7)-2.77 x 10(-4)). We also tested the two most significant SNPs (rs6435862, rs3768716) in two additional independent high-risk neuroblastoma case series, yielding combined allelic odds ratios of 1.68 each (P = 8.65 x 10(-18) and 2.74 x 10(-16), respectively). We also found significant association with known BARD1 nonsynonymous SNPs. These data show that common variation in BARD1 contributes to the etiology of the aggressive and most clinically relevant subset of human neuroblastoma."],"pubmed_title":["Copy number variation at 1q21.1 associated with neuroblastoma.","Common variations in BARD1 influence susceptibility to high-risk neuroblastoma.","Chromosome 6p22 locus associated with clinically aggressive neuroblastoma.","Integrative genomics identifies LMO1 as a neuroblastoma oncogene."],"pubmed_authors":["Maris John M JM, 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","Capasso Mario M, Devoto Marcella M, Hou Cuiping C, Asgharzadeh Shahab S, Glessner Joseph T JT, Attiyeh Edward F EF, Mosse Yael P YP, Kim Cecilia C, Diskin Sharon J SJ, Cole Kristina A KA, Bosse Kristopher K, Diamond Maura M, Laudenslager Marci M, Winter Cynthia C, Bradfield Jonathan P JP, Scott Richard H RH, Jagannathan Jayanti J, Garris Maria M, McConville Carmel C, London Wendy B WB, Seeger Robert C RC, Grant Struan F A SF, Li Hongzhe H, Rahman Nazneen N, Rappaport Eric E, Hakonarson Hakon H, Maris John M JM","Diskin Sharon J SJ, Hou Cuiping C, Glessner Joseph T JT, Attiyeh Edward F EF, Laudenslager Marci M, Bosse Kristopher K, Cole Kristina K, Mossé Yaël P YP, Wood Andrew A, Lynch Jill E JE, Pecor Katlyn K, Diamond Maura M, Winter Cynthia C, Wang Kai K, Kim Cecilia C, Geiger Elizabeth A EA, McGrady Patrick W PW, Blakemore Alexandra I F AI, London Wendy B WB, Shaikh Tamim H TH, Bradfield Jonathan J, Grant Struan F A SF, Li Hongzhe H, Devoto Marcella M, Rappaport Eric R ER, Hakonarson Hakon H, Maris John M JM","Wang Kai K, Diskin Sharon J SJ, Zhang Haitao H, Attiyeh Edward F EF, Winter Cynthia C, Hou Cuiping C, Schnepp Robert W RW, Diamond Maura M, Bosse Kristopher K, Mayes Patrick A PA, Glessner Joseph J, Kim Cecilia C, Frackelton Edward E, Garris Maria M, Wang Qun Q, Glaberson Wendy W, Chiavacci Rosetta R, Nguyen Le L, Jagannathan Jayanti J, Saeki Norihisa N, Sasaki Hiroki H, Grant Struan F A SF, Iolascon Achille A, Mosse Yael P YP, Cole Kristina A KA, Li Hongzhe H, Devoto Marcella M, McGrady Patrick W PW, London Wendy B WB, Capasso Mario M, Rahman Nazneen N, Hakonarson Hakon H, Maris John M JM"],"name_synonyms":["Genome-Wide Association, GWA Study, NUMBR, Neuroblastomas, NUMB-R, Neuroblastoma, Genome Wide Association Analysis, Whole Genome Association Study, GWA, CTG3a, NUMBLIKE., CAG3A, NBL, Genome-Wide, Genome Wide Association Studies, Genome Wide Association Scan, Genome-Wide Association Studies, Study, TNRC23, GWA Studies, Genome Wide Association Study, Studies, Association Studies, NB, Association Study, Whole Genome Association Analysis, nbl"],"description_synonyms":["Genome-Wide Association, pars sympathica divisionis autonomici systematis nervosi, Black, C|EBP-homologous protein, Neoplasms, Genome Wide Association Analysis, Whole Genome Association Study, Afro American, Benign Neoplasm, African-Americans, sympathetic part of autonomic division of nervous system, Tumor, CG30327, CHOP, Malignant, Black American, prevention, C|EBP-homologous protein 10, CG11478, Trimethyl(2-(phosphonooxy)ethyl)ammonium, embryo neoplasm, ChoP, GWA Studies, Nervous Systems, chop, Caucasian, Growth arrest and DNA-damage-inducible protein GADD153, Associations, Afro-Americans, Studies, Growth arrest and DNA damage-inducible protein GADD153, pathogenesis, African-American, whole genome., N-Trimethyl-2-aminoethylphosphonate, prevention and control, CCAAT|enhancer-binding protein homologous protein, study, DmelCG42257, GWA Study, Nervous System, American, reference sample, Malignancy, GWA, causes, Xchop, Afro Americans, Gadd153, SCAN, Sympathetic Nervous Systems, Genotypes, Genome Wide Association Scan, Genome-Wide Association Studies, Neoplasias, \"embryo neoplasm\" EXACT [CSP2005:2000-3997], Study, preventive measures, set, embryonal neoplasm, grupos, 65K, Clients, causality, CG42257, Dmel_CG30327, Malignancies, snp, genomic copy number variation, Phosphoryl-choline, DDIT-3, Negroes, Controlled, Cancer, Tumors, cg11478, Controlling, preventive therapy, Chop10, Malignant Neoplasm, grupo, copy number variation, white, embryonal tumor, O-phosphocholine, Hospital, Genome-Wide, Client, group, Choline phosphate, gadd153, Afro-American, MT, Benign, Genogroup, cancer diagnosis, Genome Wide Association Study, Phosphorylcholine, European, CG6393, Systems, Neoplasm, NB, Whole Genome Association Analysis, African American, Dmel_CG6393, O-Phosphocholine, susceptibility, African Americans, Neuroblastomas, ensemble, Neuroblastoma, Blacks, prophylaxis, System, Sympathetic, Rest, Benign Neoplasms, common, \"embryonal neoplasm\" EXACT [NCI2004_11_17:C3264], CHOP10, GADD153, Cancers, whole genome, Negro, EMBT, CHOP-10, Children, Genome Wide Association Studies, Malignant Neoplasms, Black Americans, embryonal cancer, Genogroups, Sympathetic Nervous, Patient, control, African, Association Studies, C|EBP zeta, Association Study, CEBPZ, groupe, Neoplasia, Gruppe"],"pubmed_title_synonyms":["copy number variation, NB, genomic copy number variation, Neuroblastomas, Neuroblastoma."],"pubmed_abstract_synonyms":["Genome-Wide Association, Forms, AI987914, pars sympathica divisionis autonomici systematis nervosi, Whole Genome Association Study, postnatal development, Neuroblastoma., Small Hairpin, Dlim1, Nucleotide Polymorphisms, Rbtn1, growth and development, sympathetic part of autonomic division of nervous system, Progress Reports, Risk Factor Score, Rbtn3, Rbtn2, Tumor, CG30327, prevention, Relative, CG11478, Repeat Associated siRNA, Odds Ratios, Small, Risk Factors, RBTNL2, Nervous Systems, Trans Acting, diseases, Roles, Summary Report, Associations, CG9063, Line, Concepts, diseases and disorders, RBTNL1, prevention and control, Summary Reports, Risk Ratio, CG11354, Correlates, GWA Study, DmelCG42257, human disease, thymus nucleic acid, me75, Occidental, reference sample, Progress Report, Genomes, Single Nucleotide, Childhood Cancer, Oncogeneses, BcDNA:GH03694, D17Mit170, T1, Sympathetic Nervous Systems, Genome-Wide Association Studies, genetic, Social, preventive measures, Progress, RBTN1, Rbtn-1, Field Reports, Rbtn-2, Repeat-Associated, malignant neoplasm, Health Correlates, RBTN2, RBTN3, CMH12, Role Concepts, LIM, Lim, Allele, Homo sapiens disease, Malignancies, Double-Stranded DNA, Bx, Half Cystine, deoxyribonucleic acids, DNAn, Rbtn-3, DmelCG9063, Tumors, Rhom-3, Rhom-2, Interfering RNA, BcDNA:GH04929, preventive therapy, Trans-Acting siRNA, aberrant, Zinc Cysteinate, DP, CRP3, MLP, familial, C87059, Ratios, white, Confidence, dlim-1, Double-Stranded, Tl3, Tl2, Genome-Wide, Short, (Deoxyribonucleotide)n+m, Benign, Role Concept, Investigative Report, Genome Wide Association Study, European, CG6393, Small Scan, Relative Risks, Diseases, Role, Score, Crp3, Whole Genome Association Analysis, RHOM1, Short Interfering RNA, regulator, desoxyribose nucleic acid, RHOM3, Hairpin RNA, Scan, RHOM2, ENH, Enh, Caucasians, Lines, A730077C12Rik, Dmel_CG6393, Factors, Social Risk Factors, DmelCG11354, Risk, death rate, Neuroblastomas, growth pattern, non-developmental growth, System, Sympathetic, BcDNAGH03694, Field, lmo1, Benign Neoplasms, L-Cysteine, lmo3, whole genome, Repeat Associated, 3L6, Malignant Neoplasms, Social Risk, disease, Sympathetic Nervous, Health, Report, Patient, rich, Oncogenesis, ds DNA, BB106490, White, inherited genetic, Confidence Interval, Association Study, DNA, CG10760, CMD1M, other disease, atypia, Allelomorphs, CLP, Tumorigeneses, Cysteine Hydrochloride, AI854781, DNS, (Deoxyribonucleotide)n, Genome Wide Association Analysis, Neoplasms, Benign Neoplasm, number, Malignant, presence, Deoxyribonucleic acids, LMO4, Short Hairpin RNA, GWA Studies, 1110001A05Rik, Caucasian, Investigative, Deoxyribonucleic Acid, Single Nucleotide Polymorphisms, Scan RNA, Small Scan RNA, Studies, disease or disorder, atypical, Low, Half-Cystine, Risk Factor, Interval, Intervals, Nervous System, scnRNA, Cross-Product Ratio, Populations at Risk, Risk Ratios, Malignancy, L Cysteine, GWA, Risk Score, Double Stranded, Deoxyribonucleic acid, Ratio, Population at Risk, Genome Wide Association Scan, Allelomorph, non-neoplastic, Short Hairpin, Study, Odds, Neoplasias, time of survival, Clients, Ttg2, TTG2, Polymorphisms, 65K, Ttg1, TTG1, Trans Acting siRNA, CG42257, Dmel_CG30327, Social Risk Factor, ENH1, Enh2, disorder, Enh1, snp, Enh3, (Deoxyribonucleotide)m, Investigative Reports, constitutitional genetic, tasiRNA, Controlled, Cancer, dLim1, Controlling, Cross-Product, cg11478, RNA, Trans-Acting, Etohi4, Malignant Neoplasm, cou, Nucleotide Polymorphism, DNAn+1, disorders, Cell Lines, lim1, shRNA, Factor, medical condition, defective, function, SNPs, Tumorigenesis, Risk Factor Scores, Client, Cell, Cross-Product Ratios, Small Hairpin RNA, Concept, Short Interfering, development, count in organism, Lr, MT, survival, Systems, Research Reports, Neoplasm, condition, NB, dlim1, ds-DNA, Caucasoid, Cross Product Ratio, Relative Risk, primary cancer, Small Interfering RNA, Neuroblastoma, prophylaxis, Risks, Carcinogeneses, postnatal growth, Cancers, malignant tumor, Genome Wide Association Studies, Risk Scores, Single Nucleotide Polymorphism, Relative Odds, Reports, control, Whites, siRNA, cardinality, Desoxyribonukleinsaeure, Bra, Association Studies, Single, Summary, hereditary, growth, Neoplasia, Field Report, Repeat-Associated siRNA"],"additional_accession":[]},"is_claimable":false,"name":"Neuroblastoma Genome-Wide Association Study (NBL-GWAS)","description":"<p>Neuroblastoma is a malignancy of the developing sympathetic nervous system that most commonly affects young children and is often     lethal. The etiology of this embryonal cancer is not known.</p>     <p>We have performed a whole genome scan for association of neuroblastoma with SNP genotypes and copy number variation to discover     predisposition loci.</p>     <p>We therefore initiated a genome-wide association study (GWAS) in 2007 focused on neuroblastoma patients identified through the     Children&#39;s Oncology Group (COG; 238 member institutions). Control patients for this study are children cared for at the Children&#39;s     Hospital of Philadelphia (CHOP) without a diagnosis of cancer. The study was designed to collect up to 5000 neuroblastoma cases and 10,000     controls and is powered to detect common susceptibility variants in Caucasian and African American patients. Whole genome genotyping     is being performed on the Illumina HH550 SNP array.</p>\n","dates":{"output":"2025-1-9"},"accession":"phs000124.v2.p1","cross_references":{"TAXONOMY":["9606"],"pubmed":["18463370","21124317","19536264","19412175"]}}