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DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control


Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation–positive Burkitt lymphoma, nine BCL2 translocation–positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas.

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Figure 1: Loss of methylation in lymphoma.
Figure 2: Differentially methylated regions.
Figure 3: Sphingosine-1-phosphate signaling is affected by complementary DNA mutation and methylation in germinal center B lymphomas.
Figure 4: Enrichment of transcription factor binding sites in cDMRs.
Figure 5: SMARCA4 genome architecture and protein expression.

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This study has been supported by the German Ministry of Science and Education (BMBF) in the framework of the ICGC MMML-Seq project (01KU1002A-J) and the MMML-MYC-SYS project (036166B), the European Union in the framework of the BLUEPRINT Project (HEALTH-F5-2011-282510) and the KinderKrebsInitiative Buchholz/Holm-Seppensen and LIFE (Leipzig Research Center for Civilization Diseases), Leipzig University. LIFE is funded by the European Union, the European Regional Development Fund (ERDF), the European Social Fund (ESF) and the Free State of Saxony. WGBS was additionally supported by NGFNplus (BMBF, 01GS0883) and the DKFZ–Heidelberg Center for Personalized Oncology (DKFZ-HIPO). Former grant support of MMML by the Deutsche Krebshilfe (2003–2011) is gratefully acknowledged. J.R. is supported by the Dr. Werner Jackstädt Foundation in the framework of a Junior Excellence Research Group on 'Mechanisms of B-Cell Lymphomagenesis in the Senium as Basic Principle for the Development of Age-Adjusted Therapy Regimes' (S134-10.100).

Author information





A.H., O.A., R.K., P.L., R.S., S. Hoffmann and B.R. conceived and designed the experiments. W.W., A.H., A.K.B., J.G., J.R., J.K., R.W., S.E., H.H.D.K., W.K., D.L., C. López, S.P., I.V., P.R., M. Schilhabel, M. Szczepanowski, L.T. and R.K. performed the experiments. H.K., S.H.B., M.J.B., B.H., R.E., P.F., C. Lawerenz, J.H.A.M., M. Schlesner, P.F.S., H.G.S. and S. Hoffmann performed statistical analysis. H.K., S.H.B., G.D., V.H., D.R., F.J., C.O., M.H., M. Kreuz, M. Kulis, I.N., M. Rosolowski, R.B.R., M. Schlesner, S. Hoffmann and B.R. analyzed the data. H.K., M.A.W., M.J.B., E.C.-d.-S.-P., G.D., B.H., F.J., Q.L., C.O., J.A., B.B., A.C., H.G.D., S.E., R.E., P.F., S. Haas, D.K., H.H.D.K., W.K., M. Kreuz, C. Lawerenz, D.L., M.L., R.A.F.M., J.H.A.M., J.I.M.-S., P.M., M. Rohde, P.R., M. Schilhabel, M. Schlesner, L.T., H.G.S. and S. Hoffmann contributed reagents, materials and/or analysis tools. H.K., S.H.B., W.W., A.H., P.L., R.S., S. Hoffmann and B.R. wrote the manuscript.

Corresponding authors

Correspondence to Reiner Siebert, Steve Hoffmann or Bernhard Radlwimmer.

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The authors declare no competing financial interests.

Additional information

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–23 and Supplementary Tables 1–4, 6, 9–11, 13, 14 and 16–18. (PDF 4797 kb)

Supplementary Table 5

Statistics of whole-genome sequencing. (XLSX 15 kb)

Supplementary Table 7

Annotation of DMRs. (XLSX 7648 kb)

Supplementary Table 8

Correlating DMRs. (XLSX 990 kb)

Supplementary Table 12

Statistics of transcriptome arrays. (XLSX 29 kb)

Supplementary Table 15

SWI/SNF SNVs. (XLSX 14 kb)

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Kretzmer, H., Bernhart, S., Wang, W. et al. DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control. Nat Genet 47, 1316–1325 (2015).

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