title: Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study.
abstract: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials.
  
  
  
  A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20(+)de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays.
  
  
  
  The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell-like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-κB, epigenetic, and JAK-STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses.
  
  
  
  This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. Clin Cancer Res; 22(12); 2919-28. ©2016 AACRSee related commentary by Lim and Elenitoba-Johnson, p. 2829.
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Sydney
authors.initials: S
authors.lastname: Dubois
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France. LITIS EA 4108, Normandie Université, Rouen, France.
authors.forename: Pierre-Julien
authors.initials: PJ
authors.lastname: Viailly
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Mareschal
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Bohers
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertrand
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruminy
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Maingonnat
authors.affiliation: Inserm UMRS 872, AP-HP Hôpital Necker, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Jais
authors.affiliation: Université de Lille 2, Lille, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Peyrouze
authors.affiliation: Université de Lille 2, Lille, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Figeac
authors.affiliation: Pathology, AP-HP, Hôpital Necker, Université Paris Descartes, Paris, France.
authors.forename: Thierry J
authors.initials: TJ
authors.lastname: Molina
authors.affiliation: Inserm U917, CHU Pontchaillou, Rennes, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Desmots
authors.affiliation: Inserm U917, CHU Pontchaillou, Rennes, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fest
authors.affiliation: Unité Hémopathies Lymphoïdes, AP-HP Hôpital Henri Mondor, Créteil, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Haioun
authors.affiliation: Inserm U917, CHU Pontchaillou, Rennes, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lamy
authors.affiliation: IMRB-Inserm U955, AP-HP Hôpital Henri Mondor, Créteil, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Copie-Bergman
authors.affiliation: Inserm U728, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Department of Pathology, AP-HP Hôpital Saint-Louis, Paris, France.
authors.forename: Josette
authors.initials: J
authors.lastname: Brière
authors.affiliation: Department of Pathology, Hôpital Maisonneuve-Rosemont, Montréal, Quebec, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Petrella
authors.affiliation: Laboratoire de Pathologie, AP-HP Hôpital Necker, Paris, France.
authors.forename: Danielle
authors.initials: D
authors.lastname: Canioni
authors.affiliation: Laboratoire de Pathologie, AP-HP Hôpital Saint Antoine, Paris, France.
authors.forename: Bettina
authors.initials: B
authors.lastname: Fabiani
authors.affiliation: CNRS UMR5239, Hospices Civils de Lyon, Lyon, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coiffier
authors.affiliation: Department of Hematology, AP-HP Hôpital Necker, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Delarue
authors.affiliation: Department of Hematology, Lacassagne Center, Nice, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Peyrade
authors.affiliation: CHU Dinant Godinne, UcL Namur, Yvoir, Belgium.
authors.forename: André
authors.initials: A
authors.lastname: Bosly
authors.affiliation: CHU Dinant Godinne, UcL Namur, Yvoir, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: André
authors.affiliation: Department of Oncology, Lausanne Hospital, Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ketterer
authors.affiliation: CNRS UMR5239, Hospices Civils de Lyon, Lyon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.affiliation: Inserm U955 Team 09, AP-HP Hôpital Henri Mondor, Créteil, France.
authors.forename: Karen
authors.initials: K
authors.lastname: Leroy
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France. fabrice.jardin@chb.unicancer.fr.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jardin
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D003520:Cyclophosphamide / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics; D004317:Doxorubicin / Q000627:therapeutic use; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D028884:Karyopherins / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics*; D058990:Molecular Targeted Therapy / Q000379:methods*; D015513:Oncogene Proteins / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D057285:Precision Medicine / Q000379:methods*; D011241:Prednisone / Q000627:therapeutic use; D011446:Prospective Studies; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D000069283:Rituximab; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics; D014750:Vincristine / Q000627:therapeutic use; D000073359:Exome Sequencing; D000097606:Exportin 1 Protein
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D003520:Cyclophosphamide; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D028884:Karyopherins; D015513:Oncogene Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D011241:Prednisone; D018160:Receptors, Cytoplasmic and Nuclear; D000069283:Rituximab; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014750:Vincristine; D000097606:Exportin 1 Protein; C117302:MFHAS1 protein, human; C571759:R-CHOP protocol; C051038:Inositol 1,4,5-trisphosphate 3-kinase; C076529:TNFAIP3 protein, human; C119109:GNA14 protein, human