title: Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma.
abstract: Neuroblastoma is a cancer of the sympathetic nervous system that accounts for approximately 10% of all pediatric oncology deaths. Here, we report a genome-wide association study of 2,817 neuroblastoma cases and 7,473 controls. We identified two new associations at 6q16, the first within HACE1 (rs4336470; combined P=2.7×10(-11); odds ratio 1.26, 95% confidence interval (CI) 1.18-1.35) and the second within LIN28B (rs17065417; combined P=1.2×10(-8); odds ratio 1.38, 95% CI 1.23-1.54). Expression of LIN28B and let-7 miRNA correlated with rs17065417 genotype in neuroblastoma cell lines, and we observed significant growth inhibition upon depletion of LIN28B, specifically in neuroblastoma cells that were homozygous for the risk allele. Low HACE1 and high LIN28B expression in diagnostic primary neuroblastomas were associated with worse overall survival (P=0.008 and 0.014, respectively). Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression.
authors.affiliation: Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Diskin
authors.forename: Mario
authors.initials: M
authors.lastname: Capasso
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schnepp
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Cole
authors.forename: Edward F
authors.initials: EF
authors.lastname: Attiyeh
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.forename: Maura
authors.initials: M
authors.lastname: Diamond
authors.forename: Erica L
authors.initials: EL
authors.lastname: Carpenter
authors.forename: Cynthia
authors.initials: C
authors.lastname: Winter
authors.forename: Hanna
authors.initials: H
authors.lastname: Lee
authors.forename: Jayanti
authors.initials: J
authors.lastname: Jagannathan
authors.forename: Valeria
authors.initials: V
authors.lastname: Latorre
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
mesh_terms: D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002896:Chromosomes, Human, Pair 6; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005787:Gene Frequency; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D016601:RNA-Binding Proteins; D017422:Sequence Analysis, DNA; D059467:Transcriptome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; D016601:RNA-Binding Proteins; C497506:HACE1 protein, human; D044767:Ubiquitin-Protein Ligases