New Susceptibility, Progression Loci Identified for Childhood Neuroblastoma

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(ChemotherapyAdvisor) – Two new genetic associations with neuroblastoma risk and progression have been identified, both at 6q16, according to a genome-wide association and genotyping study published in Nature Genetics.

“Low HACE1 and high LIN28B expression in diagnostic primary neuroblastomas were associated with worse overall survival (P=0.008 and 0.014, respectively),” reported senior author John M. Maris, MD, Chief of the Division of Oncology at the Children's Hospital of Philadelphia, and coauthors.

“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,” the authors wrote.

HACE1 (rs4336570) and LIN28B (rs17065417) alleles are significantly more common among children with neuroblastoma than healthy control-arm children, the study found (Odds Ratio [OR]=1.26; 95% CI, 1.23-1.54; P=2.7x10-11 for HACE1 and OR=1.38; CI, 1.23-1.54; P=1.2x10-8 for LIN28B).

HACE1 expression was significantly lower (P=0.002), and LIN28B expression was significantly higher (P=0.032) in the high-risk tumors compared to the low-risk tumors,” the authors reported.

The study included 2,817 children diagnosed with neuroblastoma or ganglioneuroblastoma and who were registered through the Children's Oncology Group (COG), and 7,473 healthy control-arm Caucasian patients recruited at well-child visits in the Children's Hospital of Philadelphia Health Care Network.

Cell line studies showed that LIN28B depletion is followed by significant growth inhibition, “specifically in neuroblastoma cells that were homozygous for the risk allele,” the authors reported.

HACE1 is epigenetically silenced by hypermethylation in most Wilms' tumors, the authors noted. LIN28B is a RNA-binding protein oncogene involved in cellular transformation when it is overexpressed, and has been putatively associated with epithelial ovarian cancer.

Neuroblastoma, a sympathetic nervous system malignancy, is responsible for 10% of childhood cancer deaths in the USA. Median age at diagnosis is 17 months. A familial variant represents approximately 1% of cases, but most cases are sporadic, and genetic and environmental risk factors for these cases remains little understood, the authors noted.

Additional predisposition loci likely remain to be discovered, they wrote.

Abstract

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