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The genetic landscape of high-risk neuroblastoma

Abstract

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per Mb (0.48 nonsilent) and notably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, and an additional 7.1% had focal deletions), MYCN (1.7%, causing a recurrent p.Pro44Leu alteration) and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1 and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies that rely on frequently altered oncogenic drivers.

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Figure 1: Landscape of genetic variation in neuroblastoma.
Figure 2: Structural variation in neuroblastoma genomes.

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Acknowledgements

We thank the Children's Oncology Group for the collection and annotation of samples for this study, and all TARGET co-investigators for scientific support of this project. Funding was provided by US National Institutes of Health grants CA98543 and CA98413 to the Children's Oncology Group, RC1MD004418 to the TARGET consortium, CA124709 (J.M.M.) and CA060104 (R.C.S.) and National Human Genome Research Institute grant U54HG003067 (E.S.L., D.A., S.B.G., G.G. and M.M.), as well as a contract from the National Cancer Institute, US National Institutes of Health (HHSN261200800001E). Additional support included a Canadian Institutes of Health Research Fellowship (T.J.P.), a Roman M. Babicki Fellowship in Medical Research at the University of British Columbia (O.M.), the Canada Research Chair in Genome Science (M.A.M.), the Giulio D'Angio Endowed Chair (J.M.M.), the Alex's Lemonade Stand Foundation (J.M.M.), the Arms Wide Open Foundation (J.M.M.) and the Cookies for Kids Foundation (J.M.M.). We thank E. Nickerson, S. Channer, K. Novik, C. Suragh and R. Roscoe for project management support. We also thank the staff of the Genome Sciences Centre Biospecimen Core, Library Construction, Sequencing and Bioinformatics teams, and the staff of the Broad Institute Biological Samples, Genome Sequencing and Genetic Analysis Platforms for their expertise in genomic processing of samples, and generating the sequencing data used in this analysis.

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Contributions

J.M.M., J. Khan, R.C.S., D.S.G. and M.A.S. conceived and led the project. M.A.M. and M.M. conceived of and supervised all aspects of the sequencing work at the British Columbia (BC) Cancer Agency Genome Sciences Centre and Broad Institute, respectively. T.J.P. and O.M. performed the analyses and interpreted the results. E.F.A., S.A., J.S.W., K.A.C., M.D., S.J.D., A.C.W., Y.P.M., L.J., T.B., Y.M., J.M.G.-F. and M.D.H. selected and characterized samples, provided disease-specific expertise in data analysis and edited the manuscript. R.S. and W.B.L. provided statistical support and analyses of clinical covariates. D.A., E.S., C. Sougnez, M.D. and J.M.G.A. provided overall project management and quality control support. S.L.C., K.C., M. Hanna, A.K., J. Kim, M.S.L., L.L., A.M., A.H.R., A.S. and C. Stewart supported analysis of somatic and germline alterations in the exome sequencing data. C.S.P. performed the pathogen discovery analysis. I.B., K.L.M., R.C., S.D.J. and J.Q. performed de novo assembly of Illumina sequencing data. Y.Z. led the library construction effort for the Illumina libraries. A.T. and Y.Z. planned the sequencing verification, and A.A. and B.K. performed the experiments. R.D.C. performed copy number analysis of genome sequencing data. M.K. performed verification of candidate rearrangements. N.T. performed gene- and exon-level quantification analysis of RNA-seq data. A.L. and A.H.K. helped interpret data provided by Complete Genomics. R.A.M. and M. Hirst led the sequencing effort for the Illumina genome and transcriptome libraries. S.B.G. and E.S.L. led the sequencing effort for the exome sequencing libraries. G.G. and S.J.M.J. supervised the bioinformatics group at the Broad Institute and BC Cancer Agency Genome Sciences Centre, respectively. T.J.P., O.M., D.S.G., M.A.M., M.M. and J.M.M. cowrote the manuscript with input from all coauthors.

Corresponding authors

Correspondence to Marco A Marra, Matthew Meyerson or John M Maris.

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Competing interests

M.M. is a paid consultant for and equity holder in Foundation Medicine, a genomics-based oncology diagnostics company, and is a paid consultant for Novartis.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 11–14 and Supplementary Figures 1–10 (PDF 4034 kb)

Supplementary Table 1

Master data table: Clinical and molecular data for all neuroblastoma cases including identifiers from other databases, sequencing technologies used, clinical and biological covariates, and matrix of mutation calls (XLSX 2887 kb)

Supplementary Table 2

Coverage: Fraction of bases in each exon with sufficient coverage for mutation detection (XLSX 184212 kb)

Supplementary Table 3

Full mutation list: All coding somatic mutations called in all cases (XLSX 2377 kb)

Supplementary Table 4

Mutation frequency correlates: Statistical comparison of mutation frequency distributions (Kolmogorov-Smirnov) when comparing cases by clinical and biological variables (XLSX 37 kb)

Supplementary Table 5

Pathogens: Counts of sequencing reads in exome capture libraries corresponding to known viruses (XLS 49 kb)

Supplementary Table 6

MutSig: Significance analysis of somatic mutation frequency in all genes and a focused set of genes listed in the Catalogue of Somatic Mutations in Cancer (XLSX 2052 kb)

Supplementary Table 7

Gene set significance analysis: Full list of pathways, member genes, mutated genes, and significance values as calculated by MutSig with and without significantly mutated genes (XLSX 381 kb)

Supplementary Table 8

Structural rearrangements: All structural variants detected in neuroblastoma genomes or transcriptomes (XLSX 16 kb)

Supplementary Table 9

Significance analysis of germline ClinVar variation: List of all genes tested for enrichment in neuroblastoma of ClinVar variants (XLSX 1622 kb)

Supplementary Table 10

Significance analysis of germline loss-of-function variants in Cancer Census, cancer syndrome, or DNA repair genes (XLSX 632 kb)

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Pugh, T., Morozova, O., Attiyeh, E. et al. The genetic landscape of high-risk neuroblastoma. Nat Genet 45, 279–284 (2013). https://doi.org/10.1038/ng.2529

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