Common genetic variants in NEFL influence gene expression and Neuroblastoma risk

Mario Capasso, Sharon Diskin, Flora Cimmino, Giovanni Acierno, Francesca Totaro, Giuseppe Petrosino, Lucia Pezone, Maura Diamond, Lee McDaniel, Hakon Hakonarson, Achille Iolascon, Marcella Devoto, John M. Maris

Research output: Contribution to journalArticle

Abstract

The genetic etiology of sporadic neuroblastoma is still largely obscure. In a genome-wide association study, we identi fi ed single-nucleotide polymorphisms (SNP) associated with neuroblastoma at the CASC15, BARD1, LMO1, DUSP12 , HSD17B12, HACE1, and LIN28B gene loci, but these explain only a small fraction of neuroblastoma heritability. Other neuroblastoma susceptibility genes are likely hidden among signals discarded by the multiple testing corrections. In this study, we evaluated eight additional genes selected as candidates for further study based on proven involvement in neuroblastoma differentiation. SNPs at these candidate genes were tested for association with disease susceptibility in 2,101 cases and 4,202 controls, with the associations found replicated in an independent cohort of 459 cases and 809 controls. Replicated associations were further studied for cis-effect using gene expression, transient overexpression, silencing, and cellular differentiation assays. The neurofilament gene NEFL harbored three SNPs associated with neuroblastoma (rs11994014: Pcombined = 0.0050; OR, 0.88; rs2979704: Pcombined = 0.0072; OR, 0.87; rs1059111: Pcombined = 0.0049; OR, 0.86). The protective allele of rs1059111 correlated with increased NEFL expression. Biologic investigations showed that ectopic overexpression of NEFL inhibited cell growth speci fi cally in neuroblastoma cells carrying the protective allele. NEFL overexpression also enhanced differentiation and impaired the proliferation and anchorage-independent growth of cells with protective allele and basal NEFL expression, while impairing invasiveness and proliferation of cells homozygous for the risk genotype. Clinically, high levels of NEFL expression in primary neuroblastoma specimens were associated with better overall survival ( P ? 0.03; HR, 0.68). Our results show that common variants of NEFL in fluence neuroblastoma susceptibility and they establish that NEFL expression influences disease initiation and progression.

Original languageEnglish
Pages (from-to)6913-6924
Number of pages12
JournalCancer Research
Volume74
Issue number23
DOIs
Publication statusPublished - Dec 1 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'Common genetic variants in NEFL influence gene expression and Neuroblastoma risk'. Together they form a unique fingerprint.

  • Cite this

    Capasso, M., Diskin, S., Cimmino, F., Acierno, G., Totaro, F., Petrosino, G., Pezone, L., Diamond, M., McDaniel, L., Hakonarson, H., Iolascon, A., Devoto, M., & Maris, J. M. (2014). Common genetic variants in NEFL influence gene expression and Neuroblastoma risk. Cancer Research, 74(23), 6913-6924. https://doi.org/10.1158/0008-5472.CAN-14-0431