Neuroblastoma, Susceptibility To, 4

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Retrieved
2019-09-22
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Trials
Genes

For a general phenotypic description and a discussion of genetic heterogeneity of neuroblastoma, see NBLST1 (256700).

Mapping

Maris et al. (2008) provided evidence for 1 or more candidate neuroblastoma susceptibility genes on chromosome 6p22. Among 1,032 neuroblastoma patients and 2,043 controls of European descent, the authors observed an association between disease and 3 SNPs on chromosome 6p22: rs6939340, rs4712653, and rs9295536, yielding p values of 1.71 x 10(-9) to 7.01 x 10(-10) (allelic odds ratio of 1.39 to 1.40). The findings suggested that common genetic variants may predispose to increased risk for neuroblastic malignant transformation.

In a genomewide analysis of 397 patients with high-risk aggressive neuroblastoma derived from the 1,032 patients in the study of Maris et al. (2008) and 2,043 controls, Capasso et al. (2009) confirmed the association of the 3 SNPs at 6p22 identified by Maris et al. (2008) as being more significantly associated with a high-risk subtype of neuroblastoma.

Molecular Genetics

Pandey et al. (2014) noted that rs6939340 is located in intron 2 of the NBAT1 gene (616206), which produces a long noncoding RNA. Cell culture and mouse xenograft models demonstrated that NBAT1 has tumor suppressor properties, such as anticell proliferation and anticell invasion. Among 93 neuroblastoma patients, high NBAT1 expression was associated with a better prognosis and longer survival compared to low NBAT1 expression. These results were validated in an independent cohort of 498 neuroblastomas, suggesting that NBAT1 may act as an independent prognostic marker in predicting event-free survival. Sequencing of genomic DNA for the rs6939340 A-to-G in high-risk tumors showed that tumors with the A/A or A/G genotype had higher expression of NBAT1 than G/G tumors. Fragments carrying the A/A genotype generated more luciferase activity in promoter vectors compared to the G/G genotype, suggesting that the region spanning the SNP may contain a putative enhancer element. High-risk patients showed hypermethylation at 5 CpG sites flanking the NBAT1 promoter, whereas low-risk patients showed hypomethylation at these sites and higher NBAT1 expression. The findings indicated that both genetic and epigenetic changes underlie differential expression of NBAT1 and suggested that these changes may be associated with different subtypes of neuroblastoma.