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

Jessica Okosun, Csaba Bödör, Jun Wang, Shamzah Araf, Cheng Yuan Yang, Chenyi Pan, Sören Boller, Davide Cittaro, Monika Bozek, Sameena Iqbal, Janet Matthews, David Wrench, Jacek Marzec, Kiran Tawana, Nikolay Popov, Ciaran O'riain, Derville O'shea, Emanuela Carlotti, Andrew Davies, Charles H. LawrieAndrás Matolcsy, Maria Calaminici, Andrew Norton, Richard J. Byers, Charles Mein, Elia Stupka, T. Andrew Lister, Georg Lenz, Silvia Montoto, John G. Gribben, Yuhong Fan, Rudolf Grosschedl, Claude Chelala, Jude Fitzgibbon

Research output: Contribution to journalArticle

Abstract

Follicular lymphoma is an incurable malignancy, 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.

Original languageEnglish
Pages (from-to)176-181
Number of pages6
JournalNature Genetics
Volume46
Issue number2
DOIs
Publication statusPublished - Feb 2014

ASJC Scopus subject areas

  • Genetics

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    Okosun, J., Bödör, C., Wang, J., Araf, S., Yang, C. Y., Pan, C., Boller, S., Cittaro, D., Bozek, M., Iqbal, S., Matthews, J., Wrench, D., Marzec, J., Tawana, K., Popov, N., O'riain, C., O'shea, D., Carlotti, E., Davies, A., ... Fitzgibbon, J. (2014). Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nature Genetics, 46(2), 176-181. https://doi.org/10.1038/ng.2856