title: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults.
abstract: The prognosis of germinal center-derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
authors.forename: Itziar
authors.initials: I
authors.lastname: Salaverria
authors.forename: Claudia
authors.initials: C
authors.lastname: Philipp
authors.forename: Ilske
authors.initials: I
authors.lastname: Oschlies
authors.forename: Christian W
authors.initials: CW
authors.lastname: Kohler
authors.forename: Markus
authors.initials: M
authors.lastname: Kreuz
authors.forename: Monika
authors.initials: M
authors.lastname: Szczepanowski
authors.forename: Birgit
authors.initials: B
authors.lastname: Burkhardt
authors.forename: Heiko
authors.initials: H
authors.lastname: Trautmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Gesk
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Andrusiewicz
authors.forename: Hilmar
authors.initials: H
authors.lastname: Berger
authors.forename: Miriam
authors.initials: M
authors.lastname: Fey
authors.forename: Lana
authors.initials: L
authors.lastname: Harder
authors.forename: Dirk
authors.initials: D
authors.lastname: Hasenclever
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.forename: Friederike
authors.initials: F
authors.lastname: Mahn
authors.forename: Idoia
authors.initials: I
authors.lastname: Martin-Guerrero
authors.forename: Shoji
authors.initials: S
authors.lastname: Pellissery
authors.forename: Christiane
authors.initials: C
authors.lastname: Pott
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
authors.forename: Alfred
authors.initials: A
authors.lastname: Reiter
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.forename: Maciej
authors.initials: M
authors.lastname: Rosolowski
authors.forename: Carsten
authors.initials: C
authors.lastname: Schwaenen
authors.forename: Harald
authors.initials: H
authors.lastname: Stein
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.forename: Swen
authors.initials: S
authors.lastname: Wessendorf
authors.forename: Rainer
authors.initials: R
authors.lastname: Spang
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002883:Chromosomes, Human, Pair 14; D002896:Chromosomes, Human, Pair 6; D005260:Female; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics* / Q000276:immunology; D018858:Germinal Center / Q000473:pathology*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011379:Prognosis; D014178:Translocation, Genetic; D055815:Young Adult; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D015514:Oncogene Proteins, Fusion; D000099218:Interferon Regulatory Factor-4