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Integrative genomics identifies LMO1 as a neuroblastoma oncogene

Nature volume 469, pages 216–220 (2011)Cite this article

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Abstract

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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Figure 1: Discovery of LMO1 at 11p15.4 as a neuroblastoma susceptibility locus.
Figure 2: LMO1 germline genotypes and somatic copy number gains are associated with mRNA and protein expression.
Figure 3: Genetic manipulation of LMO1 expression in neuroblastoma cell line models influences proliferative phenotype in an expression-specific manner.

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Gene Expression Omnibus

Data deposits

Microarray data are deposited in the GEO database under accession number GSE3960. The genotypic and phenotypic information from this study is deposited in dbGaP (http://www.ncbi.nlm.gov/gap) under accession number phs000124.v2.p1.

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Acknowledgements

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.).

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Author notes

  1. Kai Wang

    Present address: Present address: Zilkha Neurogenetic Institute, Department of Psychiatry and Preventive Medicine, University of Southern California, Los Angeles, California 90089, USA.,

  2. Kai Wang, Sharon J. Diskin and Haitao Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, 19104, Pennsylvania, USA

    Kai Wang, Haitao Zhang, Cuiping Hou, Joseph Glessner, Cecilia Kim, Edward Frackelton, Wendy Glaberson, Rosetta Chiavacci, Struan F. A. Grant & Hakon Hakonarson

  2. Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, 19104, Pennsylvania, USA

    Sharon J. Diskin, Edward F. Attiyeh, Cynthia Winter, Robert W. Schnepp, Maura Diamond, Kristopher Bosse, Patrick A. Mayes, Maria Garris, Qun Wang,  Le Nguyen, Jayanti Jagannathan, Yael P. Mosse, Kristina A. Cole & John M. Maris

  3. Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Le Nguyen, Hongzhe Li & Marcella Devoto

  4. Genetics Division, National Cancer Center Research Institute, Tokyo, 104-0045, Japan

    Norihisa Saeki & Hiroki Sasaki

  5. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Le Nguyen, Struan F. A. Grant, Yael P. Mosse, Kristina A. Cole, Marcella Devoto, Hakon Hakonarson & John M. Maris

  6. Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, 19104, Pennsylvania, USA

    Struan F. A. Grant, Marcella Devoto & Hakon Hakonarson

  7. CEINGE Biotecnologie Avanzate, Naples, 80145, Italy

    Achille Iolascon & Mario Capasso

  8. Department of Experimental Medicine, University La Sapienza, Rome, 00185, Italy

    Marcella Devoto

  9. Department of Statistics, University of Florida and Children’s Oncology Group, Gainesville, 32603, Florida, USA

    Patrick W. McGrady

  10. Dana-Farber Children’s Hospital Cancer Center and Children’s Oncology Group, Boston, 02115, Massachusetts, USA

    Wendy B. London

  11. Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, 80131, Italy

    Achille Iolascon & Mario Capasso

  12. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK

    Nazneen Rahman

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Contributions

H.H. and J.M.M. conceived the study, guided interpretation of results and helped preparation of the manuscript. K.W., H.Z. and C.H. performed SNP association analysis. K.W., S.J.D., E.F.A. and J.J. performed gene expression and copy number analysis. C.W. and K.B. performed PCR validation of gene expression data. C.W., R.W.S., K.B., P.A.M., S.J.D. and K.A.C. performed and/or analysed shRNA transfection and LMO1 overexpression experiments. N.S. and H.S. generated viral construct for human LMO1 complementary DNA. M.C. and A.I. performed the replication study on the Italian case series, and N.R. performed the replication study on the UK case series. P.W.M. and W.B.L. performed outcome and clinical covariate analyses on the Children’s Oncology Group samples. C.H., C.K., E.F., M.G., W.G. and R.C. generated the genotyping data. L.N. and M.D. helped with data analysis. S.F.A.G., Y.P.M., H.L. and M.D. advised on data interpretation. K.W. drafted the manuscript; H.H., J.M.M. and other authors edited it.

Corresponding authors

Correspondence to Hakon Hakonarson or John M. Maris.

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The authors declare no competing financial interests.

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The file contains Supplementary Materials and Methods, Supplementary Tables 1-14 and Supplementary Figures 1-8 with legends and additional references. (PDF 1614 kb)

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Wang, K., Diskin, S., Zhang, H. et al. Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature 469, 216–220 (2011). https://doi.org/10.1038/nature09609

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