Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths1,2. To identify genetic risk factors for neuroblastoma, we performed a genome-wide association study (GWAS) on 2,251 patients and 6,097 control subjects of European ancestry from four case series. Here we report a significant association within LIM domain only 1 (LMO1) at 11p15.4 (rs110419, combined P = 5.2 × 10−16, odds ratio of risk allele = 1.34 (95% confidence interval 1.25–1.44)). The signal was enriched in the subset of patients with the most aggressive form of the disease. LMO1 encodes a cysteine-rich transcriptional regulator, and its paralogues (LMO2, LMO3 and LMO4) have each been previously implicated in cancer. In parallel, we analysed genome-wide DNA copy number alterations in 701 primary tumours. We found that the LMO1 locus was aberrant in 12.4% through a duplication event, and that this event was associated with more advanced disease (P < 0.0001) and survival (P = 0.041). The germline single nucleotide polymorphism (SNP) risk alleles and somatic copy number gains were associated with increased LMO1 expression in neuroblastoma cell lines and primary tumours, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA (shRNA)-mediated depletion of LMO1 inhibited growth of neuroblastoma cells with high LMO1 expression, whereas forced expression of LMO1 in neuroblastoma cells with low LMO1 expression enhanced proliferation. These data show that common polymorphisms at the LMO1 locus are strongly associated with susceptibility to developing neuroblastoma, but also may influence the likelihood of further somatic alterations at this locus, leading to malignant progression.
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We acknowledge the Children’s Oncology Group for providing most blood and tumour specimens and clinical and outcome data (U10-CA98543 and U10-CA98413) from neuroblastoma patients. We thank G. P. Tonini for providing neuroblastoma DNA samples in the Italian replication cohort. This work was supported in part by National Institutes of Health grant R01-CA124709 (to J.M.M.), the Giulio D’Angio Endowed Chair (J.M.M.), the Alex’s Lemonade Stand Foundation (J.M.M.), the Evan Dunbar Foundation (J.M.M.), the Rally Foundation (J.M.M.), Andrew’s Army Foundation (J.M.M.), the Abramson Family Cancer Research Institute (J.M.M.), a Howard Hughes Medical Institute Research Training Fellowship (K.B.), a fellowship from Associazione Oncologia Pediatrica e Neuroblastoma (M.C.), a Research Development Award from the Cotswold Foundation (H.H.), UL1-RR024134-03 (H.H.) and an Institutional Development Award to the Center for Applied Genomics from the Children’s Hospital of Philadelphia (H.H.).
The authors declare no competing financial interests.
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