title: Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma.
abstract: Follicular lymphoma (FL) is typically an indolent disease, but 30-40% of FL cases transform into an aggressive lymphoma (tFL) with a poor prognosis. To identify the genetic changes that drive this transformation, we sequenced the exomes of 12 cases with paired FL and tFL biopsies and identified 45 recurrently mutated genes in the FL-tFL data set and 39 in the tFL cases. We selected 496 genes of potential importance in transformation and sequenced them in 23 additional tFL cases. Integration of the mutation data with copy-number abnormality (CNA) data provided complementary information. We found recurrent mutations of miR-142, which has not been previously been reported to be mutated in FL/tFL. The genes most frequently mutated in tFL included KMT2D (MLL2), CREBBP, EZH2, BCL2 and MEF2B. Many recurrently mutated genes are involved in epigenetic regulation, the Janus-activated kinase-signal transducer and activator of transcription (STAT) or the nuclear factor-κB pathways, immune surveillance and cell cycle regulation or are TFs involved in B-cell development. Of particular interest are mutations and CNAs affecting S1P-activated pathways through S1PR1 or S1PR2, which likely regulate lymphoma cell migration and survival outside of follicles. Our custom gene enrichment panel provides high depth of coverage for the study of clonal evolution or divergence.
authors.affiliation: Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bouska
authors.affiliation: Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Q
authors.identifier: 0000-0001-8502-6813
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: J
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Scuto
authors.affiliation: Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: J
authors.initials: J
authors.lastname: Vose
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Ludvigsen
authors.affiliation: Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: K
authors.initials: K
authors.lastname: Fu
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Weisenburger
authors.affiliation: Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Greiner
authors.affiliation: Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: R D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Ott
authors.affiliation: Hematopathology Unit, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: E
authors.identifier: 0000-0001-9850-9793
authors.initials: E
authors.lastname: Campo
authors.affiliation: Department of Pathology, University of Arizona, Tucson, AZ, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Rimsza
authors.affiliation: Department of Pathology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Delabie
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: Oregon Health Sciences Center, Portland, OR, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Braziel
authors.affiliation: Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: J M
authors.initials: JM
authors.lastname: Connors
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, PR China.|Department of Ecology and Evolution, University of Chicago, Chicago, IL, USA.
authors.forename: C-I
authors.initials: CI
authors.lastname: Wu
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Staudt
authors.affiliation: Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: F
authors.initials: F
authors.lastname: D'Amore
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: McKeithan
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Chan
mesh_terms: D063646:Carcinogenesis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D060965:Clonal Evolution / Q000235:genetics; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic / Q000235:genetics; D059472:Exome / Q000235:genetics; D018628:Gene Dosage; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics*; D009857:Oncogenes