Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma

Abstract

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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Figure 1: Regional association plots at the HACE1 and LIN28B loci.
Figure 2: LIN28B risk alleles correlate with increased LIN28B expression and decreased let-7 miRNA expression.
Figure 3: Transient knockdown of LIN28B influences neuroblastoma cell growth in an expression-specific manner.
Figure 4: HACE1 and LIN28B expression are associated with advanced disease and poor outcome in neuroblastoma.

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Acknowledgements

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.).

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S.J.D. and J.M.M. designed the experiment and drafted the manuscript. S.J.D. analyzed SNP data, performed SNP association studies, and analyzed mRNA and miRNA expression data. M.C. and A.I. replicated SNP associations in the Italian cohort. V.L. and M.D. replicated SNP associations in the African-American cohort. E.L.C. and H.L. confirmed LIN28B protein expression by protein blot. R.W.S. and C.W. performed experiments with siRNA-mediated knockdown of LIN28B. E.F.A. generated miRNA expression array data, including low-level summary values. K.A.C. performed RT-PCR in primary tumors. M. Diamond and C.H. organized samples and genotyped cases. J.J. participated in expression array analyses. H.H. generated and provided all control data for the GWAS. M. Devoto and H.H. contributed to overall study design. All authors commented on or contributed to the current manuscript.

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Correspondence to John M Maris.

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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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