title: Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene.
abstract: Pediatric-type follicular lymphoma (PTFL) is a variant of follicular lymphoma (FL) with distinctive clinicopathological features. Patients are predominantly young males presenting with localized lymphadenopathy; the tumor shows high-grade cytology and lacks both BCL2 expression and t(14;18) translocation. The genetic alterations involved in the pathogenesis of PTFL are unknown. Therefore, 42 PTFL (40 males and 2 females; mean age, 16 years; range, 5-31) were genetically characterized. For comparison, 11 cases of conventional t(14:18)(-) FL in adults were investigated. Morphologically, PTFL cases had follicular growth pattern without diffuse areas and characteristic immunophenotype. All cases showed monoclonal immunoglobulin (IG) rearrangement. PTFL displays low genomic complexity when compared with t(14;18)(-) FL (mean, 0.77 vs 9 copy number alterations per case; P <001). Both groups presented 1p36 alterations including TNFRSF14, but copy-number neutral loss of heterozygosity (CNN-LOH) of this locus was more frequently observed in PTFL (40% vs 9%; P =075). TNFRSF14 was the most frequently affected gene in PTFL (21 mutations and 2 deletions), identified in 54% of cases, followed by KMT2D mutations in 16%. Other histone-modifying genes were rarely affected. In contrast, t(14;18)(-) FL displayed a mutational profile similar to t(14;18)(+) FL. In 8 PTFL cases (19%), no genetic alterations were identified beyond IG monoclonal rearrangement. The genetic landscape of PTFL suggests that TNFRSF14 mutations accompanied by CNN-LOH of the 1p36 locus in over 70% of mutated cases, as additional selection mechanism, might play a key role in the pathogenesis of this disease. The genetic profiles of PTFL and t(14;18)(-) FL in adults indicate that these are two different disorders.
authors.affiliation: Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany;
authors.forename: Janine
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Hematopathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD;
authors.forename: Shunyou
authors.initials: S
authors.lastname: Gong
authors.affiliation: Department of Cellular Pathology, Barts and The London NHS Trust, London, United Kingdom;
authors.forename: Teresa
authors.initials: T
authors.lastname: Marafioti
authors.affiliation: Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany;
authors.forename: Barbara
authors.initials: B
authors.lastname: Mankel
authors.affiliation: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain;
authors.forename: Blanca
authors.initials: B
authors.lastname: Gonzalez-Farre
authors.affiliation: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain;
authors.forename: Olga
authors.initials: O
authors.lastname: Balagué
authors.affiliation: Pathology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;
authors.forename: Ana
authors.initials: A
authors.lastname: Mozos
authors.affiliation: Pathology Department, Instituto Portugues de Oncología, Lisboa, Portugal;
authors.forename: José
authors.initials: J
authors.lastname: Cabeçadas
authors.affiliation: Department of Histopathology, Guy's and St. Thomas Hospitals, London, United Kingdom;
authors.forename: Jon
authors.initials: J
authors.lastname: van der Walt
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY;
authors.forename: Daniela
authors.initials: D
authors.lastname: Hoehn
authors.affiliation: Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Department of Clinical Pathology, Robert-Bosch-Hospital and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany;
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.affiliation: Department of Pathology, All Wales Lymphoma Panel, University Hospital of Wales, Cardiff, United Kingdom;
authors.forename: Stefan
authors.initials: S
authors.lastname: Dojcinov
authors.affiliation: Hematopathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD;
authors.forename: Caoimhe
authors.initials: C
authors.lastname: Egan
authors.affiliation: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain;
authors.forename: Ferran
authors.initials: F
authors.lastname: Nadeu
authors.affiliation: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain;
authors.forename: Joan Enric
authors.initials: JE
authors.lastname: Ramis-Zaldívar
authors.affiliation: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain;
authors.forename: Guillem
authors.initials: G
authors.lastname: Clot
authors.affiliation: Hospital Universitario 12 de Octubre, Madrid, Spain;
authors.forename: Carmen
authors.initials: C
authors.lastname: Bárcena
authors.affiliation: Hospital Universitario 12 de Octubre, Madrid, Spain;
authors.forename: Vanesa
authors.initials: V
authors.lastname: Pérez-Alonso
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; and.
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; and.
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.affiliation: Department of Pathology, Instituto Nacional de Cancerologia, Mexico City, Mexico.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lome-Maldonado
authors.affiliation: Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany;
authors.forename: Irina
authors.initials: I
authors.lastname: Bonzheim
authors.affiliation: Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany;
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.affiliation: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain;
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Hematopathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD;
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain;
authors.forename: Itziar
authors.initials: I
authors.lastname: Salaverria
authors.affiliation: Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany;
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D002999:Clone Cells; D020732:Cytogenetic Analysis; D056915:DNA Copy Number Variations / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity / Q000235:genetics; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D019310:Pseudolymphoma; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics*; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: D053240:Receptors, Tumor Necrosis Factor, Member 14; C506028:TNFRSF14 protein, human