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

2013; Nature Portfolio; Volume: 46; Issue: 2 Linguagem: Inglês

10.1038/ng.2856

1546-1718

Jessica Okosun, Csaba Bödör, Jun Wang, Shamzah Araf, Cheng-Yuan Yang, Chenyi Pan, Sören Boller, Davide Cittaro, Monika Bożek, Sameena Iqbal, Janet Matthews, David Wrench, Jacek Marzec, Kiran Tawana, М. М. Попов, Ciarán Ó’Riain, Derville O’Shea, Emanuela Carlotti, Andrew Davies, Charles H. Lawrie, András Matolcsy, Maria Calaminici, A. J. Norton, Richard Byers, Charles A. Mein, Elia Stupka, T. Andrew Lister, Georg Lenz, Silvia Montoto, John G. Gribben, Yuhong Fan, Rudolf Grosschedl, Claude Chelala, Jude Fitzgibbon,

Cancer-related molecular mechanisms research

Jessica Okosun, Csaba Bödör and colleagues performed whole-genome or whole-exome sequencing on 10 follicular lymphoma and transformed follicular lymphoma pairs, followed by deep sequencing of 28 target genes in an additional 122 cases. They identify recurrent mutations in linker histone genes and genes involved in JAK-STAT signaling, NF-κB signaling and B cell development. 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.