title: Genetics of follicular lymphoma transformation.
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.
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.affiliation: Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Fangazio
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Mansi
authors.initials: M
authors.lastname: Vasishtha
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Messina
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Antony B
authors.initials: AB
authors.lastname: Holmes
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Ouillette
authors.affiliation: Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trifonov
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara 28100, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Department of Molecular Biotechnology and Health Science, Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino 10126, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tabbò
authors.affiliation: Pathology and Lymphoid Malignancies Units, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Chadburn
authors.affiliation: 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.
authors.forename: Vundavalli V
authors.initials: VV
authors.lastname: Murty
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara 28100, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Department of Molecular Biotechnology and Health Science, Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino 10126, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sami N
authors.initials: SN
authors.lastname: Malek
authors.affiliation: Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: 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.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
mesh_terms: D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D044127:Epigenesis, Genetic; D019143:Evolution, Molecular; D016259:Genes, myc; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics*; D009154:Mutation