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Cell Rep. 2014 Jan 16;6(1):130-40. doi: 10.1016/j.celrep.2013.12.027. Epub 2014 Jan 2.

Genetics of follicular lymphoma transformation.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address: lp171@columbia.edu.
2
Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.
3
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
4
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
5
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara 28100, Italy.
6
Department of Molecular Biotechnology and Health Science, Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino 10126, Italy.
7
Pathology and Lymphoid Malignancies Units, San Raffaele Scientific Institute, Milan 20132, Italy.
8
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
9
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA.
10
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA.
11
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA; Department of Genetics & Development, Columbia University, New York, NY 10032, USA; Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Electronic address: rd10@columbia.edu.

Abstract

Follicular lymphoma (FL) is an indolent disease, but 30%-40% of cases undergo histologic transformation to an aggressive malignancy, typically represented by diffuse large B cell lymphoma (DLBCL). The pathogenesis of this process remains largely unknown. Using whole-exome sequencing and copy-number analysis, we show here that the dominant clone of FL and transformed FL (tFL) arise by divergent evolution from a common mutated precursor through the acquisition of distinct genetic events. Mutations in epigenetic modifiers and antiapoptotic genes are introduced early in the common precursor, whereas tFL is specifically associated with alterations deregulating cell-cycle progression and DNA damage responses (CDKN2A/B, MYC, and TP53) as well as aberrant somatic hypermutation. The genomic profile of tFL shares similarities with that of germinal center B cell-type de novo DLBCL but also displays unique combinations of altered genes with diagnostic and therapeutic implications.

PMID:
24388756
PMCID:
PMC4100800
DOI:
10.1016/j.celrep.2013.12.027
[Indexed for MEDLINE]
Free PMC Article
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