Neuroblastoma is a cancer of the sympathetic nervous system that accounts for approximately 10% of all pediatric oncology deaths1. 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.
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We thank P. Sleiman for useful discussions regarding meta-analysis using METAL. This work was supported in part by US National Institutes of Health (NIH) grants R01-CA124709 (J.M.M.), K99-CA151869 (S.J.D.), P30-HD026979 (M. Devoto) and K08-CA136979 (K.A.C.); the Giulio D'Angio Endowed Chair (J.M.M.); the Alex's Lemonade Stand Foundation (J.M.M.); Andrew's Army Foundation (J.M.M.); the PressOn Foundation (J.M.M.); the Abramson Family Cancer Research Institute (J.M.M.); Fondazione Italiana per la Lotta al Neuroblastoma and Associazione Italiana per la Ricerca sul Cancro (M.C.); and the Center for Applied Genomics at the Children's Hospital of Philadelphia Research Institute (H.H.).
The authors declare no competing financial interests.
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Diskin, S., Capasso, M., Schnepp, R. et al. Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nat Genet 44, 1126–1130 (2012). https://doi.org/10.1038/ng.2387
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