Common Variation at 6q16 Within HACE1 and LIN28B Influences Susceptibility to Neuroblastoma

Nat Genet. 2012 Oct;44(10):1126-30. doi: 10.1038/ng.2387. Epub 2012 Sep 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromosomes, Human, Pair 6
  • Cohort Studies
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression
  • Gene Frequency
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Infant
  • Kaplan-Meier Estimate
  • Linkage Disequilibrium
  • Neuroblastoma / genetics*
  • Neuroblastoma / metabolism
  • Neuroblastoma / mortality
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide*
  • RNA Interference
  • RNA-Binding Proteins
  • Sequence Analysis, DNA
  • Transcriptome
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • DNA-Binding Proteins
  • LIN28B protein, human
  • RNA-Binding Proteins
  • HACE1 protein, human
  • Ubiquitin-Protein Ligases