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Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing

Abstract

Burkitt lymphoma is a mature aggressive B-cell lymphoma derived from germinal center B cells1. Its cytogenetic hallmark is the Burkitt translocation t(8;14)(q24;q32) and its variants, which juxtapose the MYC oncogene with one of the three immunoglobulin loci2. Consequently, MYC is deregulated, resulting in massive perturbation of gene expression3. Nevertheless, MYC deregulation alone seems not to be sufficient to drive Burkitt lymphomagenesis. By whole-genome, whole-exome and transcriptome sequencing of four prototypical Burkitt lymphomas with immunoglobulin gene (IG)-MYC translocation, we identified seven recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma4. In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. These findings suggest that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis.

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Figure 1: Spectrum of mutations in Burkitt lymphoma.
Figure 2: Mutual relationship of ID3 mutations with CCND3 (exon 5), TP53 (exons 4–10) and MYC box mutations in mBL samples without IGH-BCL2 translocation.
Figure 3: Cell cycle analysis of ID3-GFP–transfected cell lines by fluorescence-activated cell sorting (FACS).

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Gene Expression Omnibus

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Ensembl

NCBI Reference Sequence

Protein Data Bank

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Acknowledgements

This manuscript is dedicated to the memory of Karl Lennert, the founder of the Kiel classification of lymphoma, who died during the preparation of the manuscript. The authors thank O. Batic, C. Becher, C. Botz-von Drathen, A. Dietsch, J. Eils, M. Friskovec, K. Göbel, T. Grieb, S. Hengst, U. Jacobsen, T. Kaacksteen, H. Lammert, C. von der Lancken, H.-H. Müller, S. Radomski, J. Schieferstein, M. Schlapkohl, D. Schuster, S. Ölmez and L. Valles for their excellent technical support. We are grateful to G. Richter for excellent work in the coordination of the ICGC MMML-Seq Consortium and to the members of the MMML Consortium for providing extensive data of the sample analyzed within that project. We are also very grateful to all individuals who participate in this study. The project was funded by the Federal Ministry of Education and Research in Germany (BMBF) within the Program for Medical Genome Research (01KU1002A to 01KU1002J). The authors are responsible for the content of this publication. The MMML Consortium was funded by the Deutsche Krebshilfe from 2003 to 2011. Support of sequencing infrastructure by the Deutsche Forschungsgemeinschaft (DFG) and the KinderKrebsInitiative Buchholz/Holm-Seppensen is gratefully acknowledged. R.W. is the recipient of a Christoph-Schubert-Award from the KinderKrebsInitiative Buchholz/Holm-Seppensen.

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Contributions

B. Burkhardt, A.C., A.B., M. Rohde, J.L. and N.H. provided subject samples and clinical data. W.K., M.H. and P.M. coordinated and performed pathology review. D. Lenze, M. Szczepanowski, M.H. and W.K. stained and reviewed cryomaterial, prepared analytes and performed analyte quality control. D. Lenze and M.H. performed and interpreted immunoglobulin gene PCR. R.A.F.M. and H.G.D. characterized and provided cell lines. E.L., M. Schilhabel, V.H., S.P. and B.R. performed next-generation sequencing analyses, and A.R., P.R., P.L. and S.S. supervised next-generation sequencing analysis and interpreted data. C.L. coordinated transfer and data management of the sequences. M. Schlesner, B. Brors, S.H., S.H.B., P.F.S., D. Langenberger, V.H., J.O.K., T.R. and J.P. performed analysis of next-generation sequencing data, and B. Brors and R.E. conceived the statistical analysis. J.R., E.L., O.A., S.A.-K., M.P., S.L., R.B.R. and G.A. performed validation analyses. J.R. and R.W. were responsible for ID3 mutation and expression analyses. M.K., M. Rosolowski, M.L., H.T., C.P., R. Spang, K.M., R.K., R. Scholtysik, T.Z., D.K., L.T., D.H. and R. Siebert provided and analyzed data from the MMML cohort. M.K. and M. Rosolowski performed correlative and biometric analyses of the MMML cohort. J.R., M. Schlesner, M.K., S.H., R.E. and R. Siebert interpreted data and wrote the manuscript. R.E., M.H., W.K., P.R., A.R., B. Brors, O.A. and R. Siebert designed the study and coordinated the project. All authors read and approved the final manuscript.

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Correspondence to Reiner Siebert.

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Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–4, 6–8, 10, 11 and 15–21 and Supplementary Figures 1–18 (PDF 2842 kb)

Supplementary Table 5

Somatic structural variants (XLSX 14 kb)

Supplementary Table 9

Potentially protein changing somatic mutations in the four index patients (XLSX 411 kb)

Supplementary Table 12

U133A gene expression data of the potentially protein changing somatic mutations (XLSX 169 kb)

Supplementary Table 13

450K DNA methylation pattern of the potentially protein changing somatic mutations (XLSX 426 kb)

Supplementary Table 14

Results of ID3 and CCND3 mutation analysis of primary lymphoma (XLSX 17 kb)

Supplementary Table 22

Primer sequences (XLSX 14 kb)

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the ICGC MMML-Seq Project. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet 44, 1316–1320 (2012). https://doi.org/10.1038/ng.2469

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