HACE1 and LIN28B Variants Are Associated with Neuroblastoma

Familial neuroblastoma predisposition genes have recently been identified, but the genetic basis of sporadic cases, which account for 99% of neuroblastomas, remains less understood. Common variants within several genes have previously been linked to neuroblastoma but only explain a small portion of disease susceptibility. To identify additional genomic variants associated with neuroblastoma risk, Diskin and colleagues performed a genome-wide association study in over 2,000 neuroblastomas and 4,000 controls, and found 2 single-nucleotide polymorphisms (SNP) on chromosome 6q16 that reached genome-wide significance. Further analysis of this region uncovered association signals implicating 2 genes—HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) and lin-28 homolog B (LIN28B)—that were also identified in 2 independent validation cohorts. Notably, HACE1 downregulation has been observed in multiple human cancers, and Hace1-null mice are tumor prone, suggesting that risk alleles in HACE1 may affect its tumor suppressor activity. Conversely, LIN28B risk alleles may promote LIN28B oncogenic activity, as several human cancers express high levels of LIN28B and ectopic LIN28B overexpression induces cellular transformation. Consistent with this possibility, neuroblastoma cell lines that were homozygous for the LIN28B risk allele had significantly higher LIN28B expression, although no correlation between the HACE1 SNP and HACE1 expression was observed. Furthermore, LIN28B knockdown selectively inhibited the growth of neuroblastoma cells homozygous for the LIN28B risk allele. In primary tumors, LIN28B expression was significantly higher and HACE1 expression was significantly lower in high-risk tumors than in low-risk tumors, and high LIN28B expression and low HACE1 expression were associated with shorter overall survival. Although further functional studies are needed, these findings suggest that common variants affecting HACE1 and LIN28B function may contribute to neuroblastoma susceptibility.

Diskin SJ, Capasso M, Schnepp RW, Cole KA, Attiyeh EF, Hou C, et al. Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nat Genet 2012 Sept 2 [Epub ahead of print].

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