期刊
NATURE GENETICS
卷 46, 期 2, 页码 176-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2856
关键词
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资金
- Cancer Research UK through the Genomic Initiative and Programme grant [15968]
- Leukemia and Lymphoma Research
- Hungarian Scientific Research Fund [K-76204]
- Georgia Cancer Coalition Distinguished Scholar Award
- US National Institutes of Health [GM085261]
- European Hematology Association (EHA) Partner fellowship [2009/1]
- European Union and the State of Hungary
- European Social Fund in the framework [TAMOP 4.2.4. A/1-11-1-2012-0001]
- Kay Kendall Leukaemia Fund (KKLF) Junior Clinical Research Fellowship [KKL 557]
- Cancer Research UK [15968] Funding Source: researchfish
- National Institute for Health Research [ACF-2011-19-002] Funding Source: researchfish
Follicular lymphoma is an incurable malignancy(1), 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-kappa B 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-.B 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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