title: Oncogenic events rather than antigen selection pressure may be the main driving forces for relapse in diffuse large B-cell lymphomas.
abstract: Little is known on the phylogenetic relationship between diagnostic and relapse clones of diffuse large B-cell lymphoma (DLBCL). We applied high throughput sequencing (HTS) of the VDJ locus of Immunoglobulin heavy chain (IGHV) on 14 DLBCL patients with serial samples, including tumor biopsies and/or peripheral blood mononuclear cells (PBMC). Phylogenetic data were consolidated with targeted sequencing and cytogenetics. Phylogeny clearly showed that DLBCL relapse could occur according either an early or a late divergent mode. These two modes of divergence were independent from the elapsed time between diagnosis and relapse. We found no significant features for antigen selection pressure in complementary determining region both at diagnosis and relapse for 9/12 pairs and a conserved negative selection pressure for the three remaining cases. Targeted HTS and conventional cytogenetics revealed a branched vs. linear evolution for 5/5 IGHV early divergent cases, but unexpected such "oncogenetic" branched evolution could be found in at least 2/7 IGHV late divergent cases. Thus, if BCR signaling is mandatory for DLBCL emergence, oncogenetic events under chemotherapy selection pressure may be the main driving forces at relapse. Finally, circulating subclones with divergent IGHV somatic hypermutations patterns from initial biopsy could be detected in PBMC at diagnosis for 4/6 patients and, for two of them, at least one was similar to the ones found at relapse. This study highlights that oncogenetic intraclonal diversity of DLBCL should be evaluated beyond the scope a single biopsy and represents a rationale for future investigations using peripheral blood for lymphoid malignancies genotyping. Am. J. Hematol. 92:68-76, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|Department of biological hematology, Centre Hospitalier Universitaire Dupuytren, Limoges, France.
authors.forename: David
authors.initials: D
authors.lastname: Rizzo
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Pierre-Julien
authors.initials: PJ
authors.lastname: Viailly
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Mareschal
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Bohers
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|Department of pathology, Centre Henri Becquerel, Rouen, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Picquenot
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|Department of oncology genetics, Centre Henri Becquerel, Rouen, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Penther
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Sydney
authors.initials: S
authors.lastname: Dubois
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Vinciane
authors.initials: V
authors.lastname: Marchand
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertrand
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Maingonnat
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|Department of oncology genetics, Centre Henri Becquerel, Rouen, France.
authors.forename: Pascaline
authors.initials: P
authors.lastname: Etancelin
authors.affiliation: Department of biological hematology, Centre Hospitalier Universitaire Dupuytren, Limoges, France.|UMR CNRS 7276, University of Limoges, Limoges, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Feuillard
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|Department of oncology genetics, Centre Henri Becquerel, Rouen, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Bastard
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|Department of clinical hematology, Centre Henri Becquerel, Rouen, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|Department of clinical hematology, Centre Henri Becquerel, Rouen, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jardin
authors.affiliation: INSERM U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruminy
mesh_terms: D060965:Clonal Evolution; D050438:Genes, Immunoglobulin Heavy Chain; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000276:immunology; D010802:Phylogeny; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D060152:V(D)J Recombination
chemical_list: D007143:Immunoglobulin Heavy Chains