title: B-Lymphoblastic Lymphomas Evolving from Follicular Lymphomas Co-Express Surrogate Light Chains and Mutated Gamma Heavy Chains.
abstract: Follicular lymphoma (FL) is an indolent B-cell non-Hodgkin lymphoma able to transform into germinal center-type diffuse large B-cell lymphoma. We describe four extraordinary cases of FL, which progressed to TdT+CD20-precursor B-lymphoblastic lymphoma (B-LBL). Fluorescence in situ hybridization analysis showed that all four B-LBLs had acquired a MYC translocation on transformation. Comparative genomic hybridization analysis of one case demonstrated that in addition to 26 numerical aberrations that were shared between the FL and B-LBL, deletion of CDKN2A/B and 17q11, 14q32 amplification, and copy-neutral loss of heterozygosity of 9p were gained in the B-LBL cells. Whole-exome sequencing revealed mutations in FMN2, NEB, and SYNE1 and a nonsense mutation in KMT2D, all shared by the FL and B-LBL, and TNFRSF14, SMARCA2, CCND3 mutations uniquely present in the B-LBL. Remarkably, all four FL-B-LBL pairs expressed IgG. In two B-LBLs, evidence was obtained for ongoing rearrangement of IG light chain variable genes and expression of the surrogate light chain. IGHV mutation analysis showed that all FL-B-LBL pairs harbored identical or near-identical somatic mutations. From the somatic gene alterations found in the IG and non-IG genes, we conclude that the FLs and B-LBLs did not develop in parallel from early t(14;18)-positive IG-unmutated precursors, but that the B-LBLs developed from preexistent FL subclones that accumulated additional genetic damage.
authors.affiliation: Department of Pathology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, the Netherlands.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Slot
authors.affiliation: Department of Pathology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, the Netherlands.
authors.forename: Robbert
authors.initials: R
authors.lastname: Hoogeboom
authors.affiliation: Department of Pathology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Smit
authors.affiliation: Department of Pathology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, the Netherlands.
authors.forename: Thera A M
authors.initials: TA
authors.lastname: Wormhoudt
authors.affiliation: Department of Haematology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
authors.forename: Bart J
authors.initials: BJ
authors.lastname: Biemond
authors.affiliation: Department of Pathology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
authors.forename: Monique E C M
authors.initials: ME
authors.lastname: Oud
authors.affiliation: Department of Pathology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
authors.forename: Esther J M
authors.initials: EJ
authors.lastname: Schilder-Tol
authors.affiliation: Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: André B
authors.initials: AB
authors.lastname: Mulder
authors.affiliation: Bioinformatics Laboratory, Klinische Epidemiologie, Biostatistiek en Bio-informatica (KEBB), Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
authors.forename: Aldo
authors.initials: A
authors.lastname: Jongejan
authors.affiliation: Bioinformatics Laboratory, Klinische Epidemiologie, Biostatistiek en Bio-informatica (KEBB), Academic Medical Center Amsterdam, Amsterdam, the Netherlands; Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Antoine H C
authors.initials: AH
authors.lastname: van Kampen
authors.affiliation: Department of Pathology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Kluin
authors.affiliation: Department of Pathology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, the Netherlands.
authors.forename: Jeroen E J
authors.initials: JE
authors.lastname: Guikema
authors.affiliation: Department of Pathology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, the Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bende
authors.affiliation: Department of Pathology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, the Netherlands. Electronic address: c.j.vannoesel@amc.uva.nl.
authors.forename: Carel J M
authors.initials: CJ
authors.lastname: van Noesel
mesh_terms: D001402:B-Lymphocytes / Q000473:pathology; D055028:Comparative Genomic Hybridization; D056743:Cyclin D3 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D018858:Germinal Center / Q000473:pathology; D006801:Humans; D054444:Immunoglobulin Light Chains, Surrogate / Q000235:genetics* / Q000378:metabolism; D007142:Immunoglobulin gamma-Chains / Q000235:genetics* / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: C534696:CCND3 protein, human; C000614131:CDKN2A protein, human; C493966:CDKN2B protein, human; D056743:Cyclin D3; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D054444:Immunoglobulin Light Chains, Surrogate; D007142:Immunoglobulin gamma-Chains; D025542:Neurofibromin 1; D053240:Receptors, Tumor Necrosis Factor, Member 14; C084011:SMARCA2 protein, human; C506028:TNFRSF14 protein, human; D014157:Transcription Factors