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Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma

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Abstract

Follicular lymphoma is an incurable malignancy1, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma–transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.

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Figure 1: Clinical timelines and somatic mutation profiles for the discovery cases.
Figure 2: Patterns of evolution of follicular lymphoma to transformed follicular lymphoma for four cases.
Figure 3: Distribution of mutations in 28 genes in follicular lymphoma.
Figure 4: Functional analyses of mutations in linker histone HIST1H1C and EBF1.
Figure 5: Early and late mutations in follicular lymphoma and transformed follicular lymphoma.

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Acknowledgements

We are indebted to the patients for donating tumor specimens as part of this study. We would like to thank T. Chaplin-Perkins and B. Young for performing the SNP 6.0 array experiments as part of the Affymetrix Array Core Facility and G. Clark at the London Research Institute for automated DNA sequencing. This study was predominantly funded by Cancer Research UK through the Genomic Initiative and Programme grant (15968) to J.F. and was also supported by Leukemia and Lymphoma Research (grant to J.F.) and Hungarian Scientific Research Fund (Országos Tudományos Kutatási Alapprogramok, OTKA) grant K-76204 (to A.M.). Y.F. is a recipient of the Georgia Cancer Coalition Distinguished Scholar Award, and C.P. and Y.F. are, in part, supported by US National Institutes of Health grant GM085261 (to Y.F.). C.B. is a recipient of the European Hematology Association (EHA) Partner fellowship (2009/1) and was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TÁMOP 4.2.4. A/1-11-1-2012-0001 National Excellence Program. J.O. is a recipient of the Kay Kendall Leukaemia Fund (KKLF) Junior Clinical Research Fellowship (KKL 557).

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J.F., J.O. and C.B. designed and directed the study. J.O. and J.F. wrote the manuscript. T.A.L., S.M., J. Matthews and. J.G.G. identified patients for the study. and collected clinical information. S.I. prepared DNA samples. M.C., A.N., A.M. and R.J.B. conducted pathological review of specimens. J.W., D.C., J. Marzec, E.S., G.H.L., G.M. and C.C. performed the bioinformatic analysis. J.O., C.B., S.A., C.-Y.Y., S.B., C.P., M.B., D.W., K.T., N.P., C.O., D.O., E.C. and A.D. performed experiments. J.O., J.W., C.B., S.A., C.-Y.Y., S.B., G.L., Y.F. and R.G. analyzed the data. All authors read, critically reviewed and approved the manuscript.

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Correspondence to Jessica Okosun or Csaba Bödör.

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The authors declare no competing financial interests.

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Okosun, J., Bödör, C., Wang, J. et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 46, 176–181 (2014). https://doi.org/10.1038/ng.2856

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