Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
Hossein Khiabanian
Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA
Marco Fangazio
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
Mansi Vasishtha
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
Monica Messina
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
Antony B. Holmes
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
Peter Ouillette
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA
Vladimir Trifonov
Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA
Davide Rossi
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara 28100, Italy
Fabrizio Tabbò
Department of Molecular Biotechnology and Health Science, Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino 10126, Italy
Maurilio Ponzoni
Pathology and Lymphoid Malignancies Units, San Raffaele Scientific Institute, Milan 20132, Italy
Amy Chadburn
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Vundavalli V. Murty
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
Govind Bhagat
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
Gianluca Gaidano
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara 28100, Italy
Giorgio Inghirami
Department of Molecular Biotechnology and Health Science, Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino 10126, Italy
Sami N. Malek
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA
Raul Rabadan
Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA
Riccardo Dalla-Favera
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
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.
