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1. Refining diffuse large B-cell lymphoma subgroups using integrated analysis of molecular profiles

Author

Sydney Dubois, Bruno Tesson, Sylvain Mareschal, Pierre-Julien Viailly, Elodie Bohers, Philippe Ruminy, Pascaline Etancelin, Pauline Peyrouze, Christiane Copie-Bergman, Bettina Fabiani, Tony Petrella, Jean-Philippe Jais, Corinne Haioun, Gilles Salles, Thierry Jo Molina, Karen Leroy, Hervé Tilly, and Fabrice Jardin

Subjects
Medicine, Medicine (General), R5-920
Abstract

Background: Gene expression profiling (GEP), next-generation sequencing (NGS) and copy number variation (CNV) analysis have led to an increasingly detailed characterization of the genomic profiles of DLBCL. The aim of this study was to perform a fully integrated analysis of mutational, genomic, and expression profiles to refine DLBCL subtypes. A comparison of our model with two recently published integrative DLBCL classifiers was carried out, in order to best reflect the current state of genomic subtypes. Methods: 223 patients with de novo DLBCL from the prospective, multicenter and randomized LNH-03B LYSA clinical trials were included. GEP data was obtained using Affymetrix GeneChip arrays, mutational profiles were established by Lymphopanel NGS targeting 34 key genes, CNV analysis was obtained by array CGH, and FISH and IHC were performed. Unsupervised independent component analysis (ICA) was applied to GEP data and integrated analysis of multi-level molecular data associated with each component (gene signature) was performed. Findings: ICA identified 38 components reflecting transcriptomic variability across our DLBCL cohort. Many of the components were closely related to well-known DLBCL features such as cell-of-origin, stromal and MYC signatures. A component linked to gain of 19q13 locus, among other genomic alterations, was significantly correlated with poor OS and PFS. Through this integrated analysis, a high degree of heterogeneity was highlighted among previously described DLBCL subtypes. Interpretation: The results of this integrated analysis enable a global and multi-level view of DLBCL, as well as improve our understanding of DLBCL subgroups. Keywords: Diffuse large B-cell lymphoma, Independent component analysis, Transcriptomic variability, Gene signatures, prognosis

Published
2019
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2. Involvement of ORAI1/SOCE in Human AML Cell Lines and Primary Cells According to ABCB1 Activity, LSC Compartment and Potential Resistance to Ara-C Exposure

Author

Clara Lewuillon, Aurélie Guillemette, Sofia Titah, Faruk Azam Shaik, Nathalie Jouy, Ossama Labiad, Valerio Farfariello, Marie-Océane Laguillaumie, Thierry Idziorek, Adeline Barthélémy, Pauline Peyrouze, Céline Berthon, Mehmet Cagatay Tarhan, Meyling Cheok, Bruno Quesnel, Loïc Lemonnier, and Yasmine Touil

Subjects
calcium, SOCE, AML, ORAI1, ABCB1, leukemic stem cells, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Acute myeloid leukemia (AML) is a hematological malignancy with a high risk of relapse. This issue is associated with the development of mechanisms leading to drug resistance that are not yet fully understood. In this context, we previously showed the clinical significance of the ATP binding cassette subfamily B-member 1 (ABCB1) in AML patients, namely its association with stemness markers and an overall worth prognosis. Calcium signaling dysregulations affect numerous cellular functions and are associated with the development of the hallmarks of cancer. However, in AML, calcium-dependent signaling pathways remain poorly investigated. With this study, we show the involvement of the ORAI1 calcium channel in store-operated calcium entry (SOCE), the main calcium entry pathway in non-excitable cells, in two representative human AML cell lines (KG1 and U937) and in primary cells isolated from patients. Moreover, our data suggest that in these models, SOCE varies according to the differentiation status, ABCB1 activity level and leukemic stem cell (LSC) proportion. Finally, we present evidence that ORAI1 expression and SOCE amplitude are modulated during the establishment of an apoptosis resistance phenotype elicited by the chemotherapeutic drug Ara-C. Our results therefore suggest ORAI1/SOCE as potential markers of AML progression and drug resistance apparition.

Published
2022
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3. Supplementary Data from Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study

Author

Fabrice Jardin, Karen Leroy, Hervé Tilly, Gilles Salles, Nicolas Ketterer, Marc André, André Bosly, Frédéric Peyrade, Richard Delarue, Bertrand Coiffier, Bettina Fabiani, Danielle Canioni, Tony Petrella, Josette Brière, Christiane Copie-Bergman, Thierry Lamy, Corinne Haioun, Thierry Fest, Fabienne Desmots, Thierry J. Molina, Martin Figeac, Pauline Peyrouze, Jean-Philippe Jais, Catherine Maingonnat, Philippe Ruminy, Philippe Bertrand, Elodie Bohers, Sylvain Mareschal, Pierre-Julien Viailly, and Sydney Dubois

Abstract

Supplementary methods, figures, and tables Figure S1: Variant filters applied to Lymphopanel NGS data. Figure S2: Validation of variants according to SIFT and CADD scores. Figure S3: PMBL samples harbor more mutations than other DLBCL subtypes. Figure S4: Role of AID-induced SHM in DLBCL. Figure S5: Mutation frequency by subtype. Figure S6: Clustering of gene mutations according to subtype. Figure S7: Protein representations of observed mutations. Figure S8: Correlations between age and specific gene mutations. Figure S9: Prognosis according to IPI and subtype. Figure S10: Prognostic impact of gene mutations among the Lymphopanel. Table S1: Clinical characteristics of patients in our cohort. Table S2: Overview of the Lymphopanel used for NGS analysis. Table S3: Overview of pathway selection Table S4: Validation of variant filtering by an independent study of seven non-tumoral samples from DLBCL patients Table S5: Validated variants. Table S6: Lymphopanel NGS detection of genes with high AID target frequencies. Table S7: Prognostic impact of mutations in Lymphopanel genes

Published
2023

4. Supplementary Figures from Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Author

Fabrice Jardin, Hervé Tilly, Thierry J. Molina, Gilles Salles, Karen Leroy, Nicolas Ketterer, Marc André, Frédéric Peyrade, Richard Delarue, Bettina Fabiani, Christiane Copie-Bergman, Thierry Lamy, Corinne Haioun, Thierry Fest, Fabienne Desmots, Martin Figeac, Pauline Peyrouze, Bruno Tesson, Jean-Philippe Jais, Dominique Penther, Jean-Michel Picquenot, Sylvain Mareschal, Catherine Maingonnat, Vinciane Marchand, Philippe Ruminy, Philippe Bertrand, Elodie Bohers, Pierre-Julien Viailly, and Sydney Dubois

Abstract

Supplementary Figures 1-10 Figure S1. MYD88 mutation VAF according to L265P or non-L265P variants. Figure S2. Age according to MYD88 mutation status and variant among ABC patients. Figure S3. Genomic profiles of DLBCL according to the presence of MYD88 L265P or non-L265P variants. Figure S4. Relative L265P allele expression level according to L265P VAF. Figure S5. Gene expression according to MYD88 status. Figure S6. NFkB pathway gene expression according to MYD88 mutational status. Figure S7. LPS score according to subtype and downstream NFkB alterations. Figure S8. Clustering according to expression levels of 27 genes involved in LPS response and differentially expressed according to MYD88 L265P. Figure S9. TNFAIP3 and CARD11 expression according to their copy number status. Figure S10. Additional survival analyses.

Published
2023

5. Table S10. Clinical characteristics of patients with CNS relapse. from Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Author

Fabrice Jardin, Hervé Tilly, Thierry J. Molina, Gilles Salles, Karen Leroy, Nicolas Ketterer, Marc André, Frédéric Peyrade, Richard Delarue, Bettina Fabiani, Christiane Copie-Bergman, Thierry Lamy, Corinne Haioun, Thierry Fest, Fabienne Desmots, Martin Figeac, Pauline Peyrouze, Bruno Tesson, Jean-Philippe Jais, Dominique Penther, Jean-Michel Picquenot, Sylvain Mareschal, Catherine Maingonnat, Vinciane Marchand, Philippe Ruminy, Philippe Bertrand, Elodie Bohers, Pierre-Julien Viailly, and Sydney Dubois

Abstract

Clinical characteristics of the 17 patients with CNS relapse are provided, included time to CNS relapse, first-line treatment and response after first-line treatment. CR, Complete Response; PR, Partial Response; PD, Progressive Disease.

Published
2023

6. Data from Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study

Author

Fabrice Jardin, Karen Leroy, Hervé Tilly, Gilles Salles, Nicolas Ketterer, Marc André, André Bosly, Frédéric Peyrade, Richard Delarue, Bertrand Coiffier, Bettina Fabiani, Danielle Canioni, Tony Petrella, Josette Brière, Christiane Copie-Bergman, Thierry Lamy, Corinne Haioun, Thierry Fest, Fabienne Desmots, Thierry J. Molina, Martin Figeac, Pauline Peyrouze, Jean-Philippe Jais, Catherine Maingonnat, Philippe Ruminy, Philippe Bertrand, Elodie Bohers, Sylvain Mareschal, Pierre-Julien Viailly, and Sydney Dubois

Abstract

Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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 AACR.See related commentary by Lim and Elenitoba-Johnson, p. 2829

Published
2023

7. Table S1. Clinical and immunohistochemical data according to MYD88 mutation status. from Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Author

Fabrice Jardin, Hervé Tilly, Thierry J. Molina, Gilles Salles, Karen Leroy, Nicolas Ketterer, Marc André, Frédéric Peyrade, Richard Delarue, Bettina Fabiani, Christiane Copie-Bergman, Thierry Lamy, Corinne Haioun, Thierry Fest, Fabienne Desmots, Martin Figeac, Pauline Peyrouze, Bruno Tesson, Jean-Philippe Jais, Dominique Penther, Jean-Michel Picquenot, Sylvain Mareschal, Catherine Maingonnat, Vinciane Marchand, Philippe Ruminy, Philippe Bertrand, Elodie Bohers, Pierre-Julien Viailly, and Sydney Dubois

Abstract

All relevant clinical data is included. Immunohistochemical results for BCL2, CD10, BCL6, MUM1, FOXP1, IgM and MYC are transcribed: 0 indicates negativity and 1 indicates positivity. For BCL2 and MYC, positivity is according to a threshold of 50% or 40% respectively.

Published
2023

8. Data from Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Author

Fabrice Jardin, Hervé Tilly, Thierry J. Molina, Gilles Salles, Karen Leroy, Nicolas Ketterer, Marc André, Frédéric Peyrade, Richard Delarue, Bettina Fabiani, Christiane Copie-Bergman, Thierry Lamy, Corinne Haioun, Thierry Fest, Fabienne Desmots, Martin Figeac, Pauline Peyrouze, Bruno Tesson, Jean-Philippe Jais, Dominique Penther, Jean-Michel Picquenot, Sylvain Mareschal, Catherine Maingonnat, Vinciane Marchand, Philippe Ruminy, Philippe Bertrand, Elodie Bohers, Pierre-Julien Viailly, and Sydney Dubois

Abstract

Purpose: MYD88 mutations, notably the recurrent gain-of-function L265P variant, are a distinguishing feature of activated B-cell like (ABC) diffuse large B-cell lymphoma (DLBCL), leading to constitutive NFκB pathway activation. The aim of this study was to examine the distinct genomic profiles of MYD88-mutant DLBCL, notably according to the presence of the L265P or other non-L265P MYD88 variants.Experimental Design: A cohort of 361 DLBCL cases (94 MYD88 mutant and 267 MYD88 wild-type) was submitted to next-generation sequencing (NGS) focusing on 34 genes to analyze associated mutations and copy number variations, as well as gene expression profiling, and clinical and prognostic analyses.Results: Importantly, we highlighted different genomic profiles for MYD88 L265P and MYD88 non-L265P–mutant DLBCL, shedding light on their divergent backgrounds. Clustering analysis also segregated subgroups according to associated genetic alterations among patients with the same MYD88 mutation. We showed that associated CD79B and MYD88 L265P mutations act synergistically to increase NFκB pathway activation, although the majority of MYD88 L265P–mutant cases harbors downstream NFκB alterations, which can predict BTK inhibitor resistance. Finally, although the MYD88 L265P variant was not an independent prognostic factor in ABC DLBCL, associated CD79B mutations significantly improved the survival of MYD88 L265P–mutant ABC DLBCL in our cohort.Conclusions: This study highlights the relative heterogeneity of MYD88-mutant DLBCL, adding to the field's knowledge of the theranostic importance of MYD88 mutations, but also of associated alterations, emphasizing the usefulness of genomic profiling to best stratify patients for targeted therapy. Clin Cancer Res; 23(9); 2232–44. ©2016 AACR.

Published
2023

9. Supplementary Data from Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Author

Fabrice Jardin, Hervé Tilly, Thierry J. Molina, Gilles Salles, Karen Leroy, Nicolas Ketterer, Marc André, Frédéric Peyrade, Richard Delarue, Bettina Fabiani, Christiane Copie-Bergman, Thierry Lamy, Corinne Haioun, Thierry Fest, Fabienne Desmots, Martin Figeac, Pauline Peyrouze, Bruno Tesson, Jean-Philippe Jais, Dominique Penther, Jean-Michel Picquenot, Sylvain Mareschal, Catherine Maingonnat, Vinciane Marchand, Philippe Ruminy, Philippe Bertrand, Elodie Bohers, Pierre-Julien Viailly, and Sydney Dubois

Abstract

Supplementary methods, supplementary figure & table legends, and supplementary tables 3, 4, 8 & 9. Table S3: Overview of the Lymphopanel used for NGS analysis. Table S4: Overview of pathway selection Table S8. Genes involved in the LPS score. Table S9. Expression levels of genes involved in response to LPS stimulation according to MYD88 L265P.

Published
2023

10. Table S7. Immunohistochemical markers and gene rearrangements according to MYD88 variants. from Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Author

Fabrice Jardin, Hervé Tilly, Thierry J. Molina, Gilles Salles, Karen Leroy, Nicolas Ketterer, Marc André, Frédéric Peyrade, Richard Delarue, Bettina Fabiani, Christiane Copie-Bergman, Thierry Lamy, Corinne Haioun, Thierry Fest, Fabienne Desmots, Martin Figeac, Pauline Peyrouze, Bruno Tesson, Jean-Philippe Jais, Dominique Penther, Jean-Michel Picquenot, Sylvain Mareschal, Catherine Maingonnat, Vinciane Marchand, Philippe Ruminy, Philippe Bertrand, Elodie Bohers, Pierre-Julien Viailly, and Sydney Dubois

Abstract

Statistically significant differences (p

Published
2023

11. Table S5. Cohort variants. from Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Author

Fabrice Jardin, Hervé Tilly, Thierry J. Molina, Gilles Salles, Karen Leroy, Nicolas Ketterer, Marc André, Frédéric Peyrade, Richard Delarue, Bettina Fabiani, Christiane Copie-Bergman, Thierry Lamy, Corinne Haioun, Thierry Fest, Fabienne Desmots, Martin Figeac, Pauline Peyrouze, Bruno Tesson, Jean-Philippe Jais, Dominique Penther, Jean-Michel Picquenot, Sylvain Mareschal, Catherine Maingonnat, Vinciane Marchand, Philippe Ruminy, Philippe Bertrand, Elodie Bohers, Pierre-Julien Viailly, and Sydney Dubois

Abstract

This table presents all variants identified among our cohort by Lymphopanel NGS. Variant type and variant allele frequency (VAF) are indicated.

Published
2023

12. Table S6. Cohort copy number variations. from Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Author

Fabrice Jardin, Hervé Tilly, Thierry J. Molina, Gilles Salles, Karen Leroy, Nicolas Ketterer, Marc André, Frédéric Peyrade, Richard Delarue, Bettina Fabiani, Christiane Copie-Bergman, Thierry Lamy, Corinne Haioun, Thierry Fest, Fabienne Desmots, Martin Figeac, Pauline Peyrouze, Bruno Tesson, Jean-Philippe Jais, Dominique Penther, Jean-Michel Picquenot, Sylvain Mareschal, Catherine Maingonnat, Vinciane Marchand, Philippe Ruminy, Philippe Bertrand, Elodie Bohers, Pierre-Julien Viailly, and Sydney Dubois

Abstract

This table presents all CNVs identified among our cohort using the ONCOCNV software. Duplication was considered when copy number was superior to 2 and deletion was considered when copy number was inferior to 2. False discovery rate (FDR) cutoff was set at 0.01.

Published
2023

13. Table S2. Cell of origin according to MYD88 mutations. from Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Author

Fabrice Jardin, Hervé Tilly, Thierry J. Molina, Gilles Salles, Karen Leroy, Nicolas Ketterer, Marc André, Frédéric Peyrade, Richard Delarue, Bettina Fabiani, Christiane Copie-Bergman, Thierry Lamy, Corinne Haioun, Thierry Fest, Fabienne Desmots, Martin Figeac, Pauline Peyrouze, Bruno Tesson, Jean-Philippe Jais, Dominique Penther, Jean-Michel Picquenot, Sylvain Mareschal, Catherine Maingonnat, Vinciane Marchand, Philippe Ruminy, Philippe Bertrand, Elodie Bohers, Pierre-Julien Viailly, and Sydney Dubois

Abstract

COO information according to the three techniques used in this study is given according to the various MYD88 variants present in our cohort.

Published
2023

14. Targeting RUNX1 in acute myeloid leukemia: preclinical innovations and therapeutic implications

Author

Adeline Barthelemy, Meyling Cheok, Nicolas Duployez, Pauline Peyrouze, Claude Preudhomme, Laurène Fenwarth, and Fanny Gonzales

Subjects
0301 basic medicine, BRD4, Clinical Biochemistry, Antineoplastic Agents, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Germline mutation, Genome editing, hemic and lymphatic diseases, Drug Discovery, Animals, Humans, Medicine, Molecular Targeted Therapy, Transcription factor, Germ-Line Mutation, Pharmacology, business.industry, Myeloid leukemia, Prognosis, Pre-clinical development, Survival Rate, Leukemia, Myeloid, Acute, Haematopoiesis, 030104 developmental biology, RUNX1, chemistry, 030220 oncology & carcinogenesis, Core Binding Factor Alpha 2 Subunit, Mutation, embryonic structures, Disease Progression, Cancer research, Molecular Medicine, business
Abstract

Introduction: RUNX1 is an essential transcription factor for normal and malignant hematopoiesis. RUNX1 forms a heterodimeric complex with CBFB. Germline mutations and somatic alterations (i.e. translocations, mutations and abnormal expression) are frequently associated with acute myeloid leukemia (AML) with RUNX1 mutations conferring unfavorable prognosis. Therefore, RUNX1 constitutes a potential innovative and interesting therapeutic target. In this review, we discuss recent therapeutic advances of RUNX1 targeting in AML.Areas covered: Firstly, we cover the clinical basis for RUNX1 targeting. We have subdivided recent therapeutic approaches either by common biochemical pathways or by similar pharmacological targets. Genome editing of RUNX1 induces anti-leukemic effects; however, off-target events prohibit clinical use. Several molecules inhibit the interaction between RUNX1/CBFB and control AML development and progression. BET protein antagonists target RUNX1 (i.e. specific BET inhibitors, BRD4 shRNRA, proteolysis targeting chimeras (PROTAC) or expression-mimickers). All these molecules improve survival in mutant RUNX1 AML preclinical models.Expert opinion: Some of these novel molecules have shown encouraging anti-leukemic potency at the preclinical stage. A better understanding of RUNX1 function in AML development and progression and its key downstream pathways, may result in more precise and more efficient RUNX1 targeting therapies.

Published
2021

15. Refining diffuse large B-cell lymphoma subgroups using integrated analysis of molecular profiles

Author

Bettina Fabiani, Sylvain Mareschal, Pascaline Etancelin, Tony Petrella, Fabrice Jardin, Bruno Tesson, Sydney Dubois, Jean-Philippe Jais, Christiane Copie-Bergman, Gilles Salles, Elodie Bohers, Corinne Haioun, Pierre-Julien Viailly, Thierry Jo Molina, Philippe Ruminy, Karen Leroy, Hervé Tilly, Pauline Peyrouze, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Carnot CALYM [Pierre-Benite], Synergie Lyon Cancer-Platform of Bioinformatics-Gilles Thomas, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Université Lille 2 - Faculté de Médecine, INSERM U955, équipe 9, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de pathologie, Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département d'Hématologie, Institut Carnot Lymphome (CALYM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculté de Médecine Henri Warembourg - Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Centre de pathologie [Dijon]

Subjects
0301 basic medicine, Male, Research paper, Key genes, Transcriptomic variability, DNA Copy Number Variations, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Locus (genetics), Computational biology, Independent component analysis, Biology, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], hemic and lymphatic diseases, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Copy-number variation, Gene signatures, prognosis, Genetic Association Studies, lcsh:R5-920, Gene Expression Profiling, lcsh:R, Gene signatures, Chromosome Mapping, Computational Biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Molecular Sequence Annotation, General Medicine, Diffuse large B-cell lymphoma, Gene signature, medicine.disease, Immunohistochemistry, Gene expression profiling, 030104 developmental biology, 030220 oncology & carcinogenesis, Affymetrix genechip, Female, prognosis, Lymphoma, Large B-Cell, Diffuse, lcsh:Medicine (General)
Abstract

Background: Gene expression profiling (GEP), next-generation sequencing (NGS) and copy number variation (CNV) analysis have led to an increasingly detailed characterization of the genomic profiles of DLBCL. The aim of this study was to perform a fully integrated analysis of mutational, genomic, and expression profiles to refine DLBCL subtypes. A comparison of our model with two recently published integrative DLBCL classifiers was carried out, in order to best reflect the current state of genomic subtypes. Methods: 223 patients with de novo DLBCL from the prospective, multicenter and randomized LNH-03B LYSA clinical trials were included. GEP data was obtained using Affymetrix GeneChip arrays, mutational profiles were established by Lymphopanel NGS targeting 34 key genes, CNV analysis was obtained by array CGH, and FISH and IHC were performed. Unsupervised independent component analysis (ICA) was applied to GEP data and integrated analysis of multi-level molecular data associated with each component (gene signature) was performed. Findings: ICA identified 38 components reflecting transcriptomic variability across our DLBCL cohort. Many of the components were closely related to well-known DLBCL features such as cell-of-origin, stromal and MYC signatures. A component linked to gain of 19q13 locus, among other genomic alterations, was significantly correlated with poor OS and PFS. Through this integrated analysis, a high degree of heterogeneity was highlighted among previously described DLBCL subtypes. Interpretation: The results of this integrated analysis enable a global and multi-level view of DLBCL, as well as improve our understanding of DLBCL subgroups. Keywords: Diffuse large B-cell lymphoma, Independent component analysis, Transcriptomic variability, Gene signatures, prognosis

Published
2019

16. Detection of a new heterozygous germline ETV6 mutation in a case with hyperdiploid acute lymphoblastic leukemia

Author

Nicolas Duployez, Yves Bertrand, Thomas Boyer, Alice Marceau-Renaut, Sandrine Geffroy, Pauline Peyrouze, Sophie Lejeune, Wadih Abou Chahla, Nathalie Grardel, Gérard Michel, Guillaume Letizia, Brigitte Nelken, and Claude Preudhomme

Subjects
Male, 0301 basic medicine, Heterozygote, Adolescent, Somatic cell, DNA Mutational Analysis, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Germline, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, Germline mutation, hemic and lymphatic diseases, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Germ-Line Mutation, Mutation, Proto-Oncogene Proteins c-ets, Hematology, General Medicine, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Repressor Proteins, Transplantation, ETV6, 030104 developmental biology, Cancer research, 030215 immunology
Abstract

ETV6 is a target of recurrent aberrations in sporadic and familial acute lymphoblastic leukemia (ALL). Here, we report on a new pedigree with a germline ETV6 mutation in which the index patient and his father developed high hyperdiploid (HeH) ALL and polycythemia vera at age 13 and 51, respectively. The index patient achieved durable complete remission without transplantation but had persistent moderate thrombocytopenia without bleeding tendency. To determine the prevalence of ETV6 alterations in HeH-ALL, we screened 81 unrelated subjects with HeH-ALL by single nucleotide polymorphism array and high-throughput sequencing for the ETV6 gene. Overall, ETV6 microdeletions and mutations were identified in 9% of cases, all of which were somatic and considered as secondary events. Apart from the index patient, no germline ETV6 aberration was identified. Finally, we reviewed the literature for ETV6 germline aberrations and predispositions to ALL.

Published
2017

17. Clinical significance of abcb1 in acute myeloid leukemia:a comprehensive study

Author

Hervé Dombret, Christophe Roumier, Stéphane de Botton, Céline Berthon, Claude Preudhomme, Thomas Boyer, Adriana Plesa, Carole Delattre, Nicolas Pottier, Pauline Peyrouze, Alice Marceau-Renaut, Marc Wetterwald, Pascale Lepelley, Fanny Gonzales, Olivier Nibourel, Adeline Barthelemy, Isabelle Plantier, Soizic Guihard, Meyling Cheok, CNRS, Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc], Service d'Hématologie Cellulaire [Lille], Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - EA 4483, Impact de l'environnement chimique sur la santé humaine - ULR 4483 [IMPECS], Institut Gustave Roussy [IGR], Université Paris Diderot - Paris 7 [UPD7], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, CHU Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'hématologie (CH de Dunkerque), Centre Hospitalier Dunkerque, CHU Roubaix, Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), and Université Paris Diderot - Paris 7 (UPD7)

Subjects
0301 basic medicine, Cancer Research, NPM1, Gemtuzumab ozogamicin, medicine.medical_treatment, [SDV]Life Sciences [q-bio], CD33, ABCB1, acute myeloid leukemia, prognosis, gene expression, drug resistance, CD34, Drug resistance, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, medicine, BAALC, Chemotherapy, business.industry, Myeloid leukemia, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, business, medicine.drug
Abstract

ABCB1 is a member of the ATP binding cassette transporter family and high ABCB1 activity is considered as a poor prognostic factor in acute myeloid leukemia (AML) treated with intensive chemotherapy, its direct relation with drug resistance remains unclear. We evaluated ABCB1 activity in relation with clinical parameters and treatment response to standard chemotherapy in 321 patients with de novo AML. We assessed multiple clinical relationships of ABCB1 activity&mdash, ex vivo drug resistance, gene expression, and the ABCB1 inhibitor quinine were evaluated. ABCB1 activity was observed in 58% of AML and was linked to low white blood cell count, high expression of CD34, absence of FLT3-ITD, and absence of mutant NPM1. Moreover, ABCB1 activity was associated with worse overall- and event-free survival. However, ABCB1 activity did not directly lead to ex vivo drug resistance to anthracyclines. We found that ABCB1 was highly correlated with gene expressions of BAALC, CD34, CD200, and CD7, indicating that ABCB1 expression maybe a passenger characteristic of high-risk AML. Furthermore, ABCB1 was inversely correlated to HOX cluster genes and CD33. Thus, low ABCB1 AML patients benefited specifically from anti-CD33 treatment by gemtuzumab ozogamicin in addition to standard chemotherapy. We showed prognostic importance of ABCB1 gene expression, protein expression, and activity. Furthermore, ABCB1 was not directly linked to drug resistance, ABCB1 inhibition did not improve outcome of high ABCB1 AML patients and thus high ABCB1 may represent a passenger characteristic of high-risk AML.

Published
2019

18. Copy-number analysis identified new prognostic marker in acute myeloid leukemia

Author

Agnès Paquet, Olivier Nibourel, Soizic Guihard, C Demay, Claude Preudhomme, Karine Celli-Lebras, Pauline Peyrouze, Jean Soulier, Christophe Roumier, Aline Renneville, Raouf Ben Abdelali, Pascal Barbry, Antonio José Alberdi, Sylvie Castaigne, Christine Terré, Nicolas Pottier, Hervé Dombret, Sandrine Geffroy, Samuel Quentin, Meyling Cheok, and Bruno Quesnel

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Myeloid, DNA Copy Number Variations, Gene Dosage, Copy number analysis, Genome-wide association study, Bioinformatics, Malignancy, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, Proportional Hazards Models, Hematology, business.industry, Myeloid leukemia, Genomics, Middle Aged, Genes, p53, Prognosis, medicine.disease, Leukemia, Myeloid, Acute, Leukemia, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Mutation, Cytarabine, Female, business, Genome-Wide Association Study, medicine.drug
Abstract

Recent advances in genomic technologies have revolutionized acute myeloid leukemia (AML) understanding by identifying potential novel actionable genomic alterations. Consequently, current risk stratification at diagnosis not only relies on cytogenetics, but also on the inclusion of several of these abnormalities. Despite this progress, AML remains a heterogeneous and complex malignancy with variable response to current therapy. Although copy-number alterations (CNAs) are accepted prognostic markers in cancers, large-scale genomic studies aiming at identifying specific prognostic CNA-based markers in AML are still lacking. Using 367 AML, we identified four recurrent CNA on chromosomes 11 and 21 that predicted outcome even after adjusting for standard prognostic risk factors and potentially delineated two new subclasses of AML with poor prognosis. ERG amplification, the most frequent CNA, was related to cytarabine resistance, a cornerstone drug of AML therapy. These findings were further validated in The Cancer Genome Atlas data. Our results demonstrate that specific CNA are of independent prognostic relevance, and provide new molecular information into the genomic basis of AML and cytarabine response. Finally, these CNA identified two potential novel risk groups of AML, which when confirmed prospectively, may improve the clinical risk stratification and potentially the AML outcome.

Published
2016

19. Tetraspanin CD81 is an adverse prognostic marker in acute myeloid leukemia

Author

Pauline Peyrouze, Céline Berthon, Christophe Roumier, Soizic Guihard, Thomas Boyer, Hélène Behal, Claude Preudhomme, Alain Duhamel, Fanny Gonzales, Bruno Quesnel, Catherine Roche-Lestienne, Meyling Cheok, CHU Lille, Inserm, Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc], and Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS]

Subjects
0301 basic medicine, Oncology, Male, Cell, Kaplan-Meier Estimate, Leukocyte Count, 0302 clinical medicine, CD81, Tetraspanin, hemic and lymphatic diseases, Granulocyte Precursor Cells, Multiple myeloma, medicine.diagnostic_test, Age Factors, Myeloid leukemia, Nuclear Proteins, Middle Aged, Prognosis, Leukemia, Myeloid, Acute, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, Female, prognosis, flow cytometry, tetraspanin, acute myeloid leukemia, Nucleophosmin, Research Paper, Adult, medicine.medical_specialty, Disease-Free Survival, Flow cytometry, Tetraspanin 28, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Biomarkers, Tumor, Humans, Aged, business.industry, Cell Membrane, Cytogenetics, medicine.disease, 030104 developmental biology, Immunology, Mutation, business, Follow-Up Studies
Abstract

CD81 is a cell surface protein which belongs to the tetraspanin family. While in multiple myeloma its expression on plasma cells is associated with worse prognosis, this has not yet been explored in acute myeloid leukemia (AML). We measured membrane expression of CD81 on AML cells at diagnosis, evaluated its association with AML characteristics and its influence on patient outcome after intensive chemotherapy in a cohort of 134 patients. CD81 was detected in 92/134 (69%) patients. Patients with AML expressing CD81 had elevated leukocyte count (P=0.02) and were more likely classified as intermediate or adverse-risk by cytogenetics (P

Published
2016

20. Whole exome sequencing of relapsed/refractory patients expands the repertoire of somatic mutations in diffuse large B-cell lymphoma

Author

Corinne Haioun, Pierre-Julien Viailly, Gilles Salles, Catherine Maingonnat, Thierry Jo Molina, Sylvain Mareschal, Bruno Tesson, Elodie Bohers, Jean-Philippe Jais, Christiane Copie-Bergman, Philippe Ruminy, Fabrice Jardin, Thierry Lecroq, Philippe Bertrand, Sydney Dubois, Thierry Fest, Pauline Peyrouze, Karen Leroy, and Hervé Tilly

Subjects
0301 basic medicine, Cancer Research, Candidate gene, Germinal center, Biology, medicine.disease, GNA13, 3. Good health, Lymphoma, 03 medical and health sciences, 030104 developmental biology, CDKN2A, hemic and lymphatic diseases, Genetics, medicine, Cancer research, Exome, Diffuse large B-cell lymphoma, Exome sequencing
Abstract

Despite the many efforts already spent to enumerate somatic mutations in diffuse large B-cell lymphoma (DLBCL), previous whole-genome and whole-exome studies conducted on patients of mixed outcomes failed at characterizing the 30% of patients who will relapse or resist current immunochemotherapies. To address this issue, we performed whole-exome sequencing of normal/tumoral DNA pairs in 14 relapsed/refractory (R/R) patients subclassified by full-transcriptome arrays (six activated B-cell like, three germinal center B-cell like, and five primary mediastinal B-cell lymphomas), from the LNH-03 LYSA clinical trial program. Aside from well-known DLBCL features, gene and pathway level recurrence analyses proposed several interesting leads including TBL1XR1 and activating mutations in IRF4 or in the insulin regulation pathway. Sequencing-based copy number analysis defined 23 short recurrently altered regions involving genes such as REL, CDKN2A, HYAL2, and TP53. Moreover, it highlighted mutations in genes such as GNA13, CARD11, MFHAS1, and PCLO as associated with secondary variant allele amplification events. The five primary mediastinal B-cell lymphomas (PMBL), while unexpected in a R/R cohort, showed a significantly higher mutation rate (P = 0.003) and provided many insights on this classical Hodgkin lymphoma related subtype. Novel genes such as XPO1, MFHAS1, and ITPKB were found particularly mutated, along with various cytokine-based signaling pathways. Among these analyses, somatic events in the NF-κB pathway were found preponderant in the three DLBCL subtypes, confirming its major implication in DLBCL aggressiveness and pinpointing several new candidate genes.

Published
2015

21. Flow Cytometry to Estimate Leukemia Stem Cells in Primary Acute Myeloid Leukemia and in Patient-derived-xenografts, at Diagnosis and Follow Up

Author

Adriana Plesa, Claude Preudhomme, Pauline Peyrouze, Fanny Gonzales, Adeline Barthelemy, Soizic Guihard, Meyling Cheok, Bruno Quesnel, Christophe Roumier, and Thomas Boyer

Subjects
0301 basic medicine, Adult, Cancer Research, Myeloid, General Chemical Engineering, CD34, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Animals, Humans, Progenitor cell, General Immunology and Microbiology, General Neuroscience, Myeloid leukemia, medicine.disease, Flow Cytometry, Minimal residual disease, Leukemia, Haematopoiesis, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Neoplastic Stem Cells, sense organs, Stem cell, Follow-Up Studies
Abstract

Acute myeloid leukemia (AML) is a heterogeneous, and if not treated, fatal disease. It is the most common cause of leukemia-associated mortality in adults. Initially, AML is a disease of hematopoietic stem cells (HSC) characterized by arrest of differentiation, subsequent accumulation of leukemia blast cells, and reduced production of functional hematopoietic elements. Heterogeneity extends to the presence of leukemia stem cells (LSC), with this dynamic cell compartment evolving to overcome various selection pressures imposed upon during leukemia progression and treatment. To further define the LSC population, the addition of CD90 and CD45RA allows the discrimination of normal HSCs and multipotent progenitors within the CD34+CD38- cell compartment. Here, we outline a protocol to detect simultaneous expression of several putative LSC markers (CD34, CD38, CD45RA, CD90) on primary blast cells of human AML by multiparametric flow cytometry. Furthermore, we show how to quantify three progenitor populations and a putative LSC population with increasing degree of maturation. We confirmed the presence of these populations in corresponding patient-derived-xenografts. This method of detection and quantification of putative LSC may be used for clinical follow-up of chemotherapy response (i.e., minimal residual disease), as residual LSC may cause AML relapse.

Published
2018

22. Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P-Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Author

Thierry Jo Molina, Fabrice Jardin, Marc André, Richard Delarue, Sylvain Mareschal, Philippe Bertrand, Thierry Fest, Corinne Haioun, Pierre-Julien Viailly, Martin Figeac, Philippe Ruminy, Dominique Penther, Vinciane Marchand, Sydney Dubois, Frederic Peyrade, Jean-Michel Picquenot, Karen Leroy, Jean-Philippe Jais, Christiane Copie-Bergman, Bruno Tesson, Catherine Maingonnat, Bettina Fabiani, Elodie Bohers, Fabienne Desmots, Hervé Tilly, Nicolas Ketterer, Thierry Lamy, Pauline Peyrouze, Gilles Salles, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Res Ctr, Institut Curie, Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Lille 2 - Faculté de Médecine, Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement français du sang [Rennes] (EFS Bretagne), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d’immunologie, de thérapie cellulaire et d’hématopoïèse, Hôpital Pontchaillou, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pathologie [Mondor], Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Cliniques Universitaires UCL Mont-Godinne, Department of Oncology, Lausanne Hospital, Lausanne Hospital, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Necker], Service d'informatique médicale et biostatistiques [CHU Necker], Institut Carnot Lymphome (CALYM), Faculté de Médecine Henri Warembourg - Université de Lille, Interactions cellulaires et moléculaires (ICM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Microenvironnement et cancer (MiCa), Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de Pathologie [CHU Necker], Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe d'étude des proliférations lymphoïdes ( GPL ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes ( LITIS ), Université Le Havre Normandie ( ULH ), Normandie Université ( NU ) -Normandie Université ( NU ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut national des sciences appliquées Rouen Normandie ( INSA Rouen Normandie ), Normandie Université ( NU ), HEMATOLOGIE, CRLCC Henri Becquerel, Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Dept Translat Res, Breast Canc Biol Grp, Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Institut pour la recherche sur le cancer de Lille [Lille] ( IRCL ) -Université de Lille, Droit et Santé, Microenvironment, Cell Differentiation, Immunology and Cancer ( MICMAC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement français du sang [Rennes] ( EFS Bretagne ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre d'Investigation Clinique [Rennes] ( CIC ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Carnot CALYM [Pierre-Benite], Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Université Côte d'Azur (UCA)-UNICANCER, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-IFR140-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Sorbonne Université (SU)-CHU Saint-Antoine [APHP], Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU), MINES ParisTech - École nationale supérieure des mines de Paris, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Oncology, 0301 basic medicine, Cancer Research, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Bioinformatics, medicine.disease_cause, Biochemistry, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Targeted therapy, 0302 clinical medicine, CDKN2A, hemic and lymphatic diseases, Copy-number variation, Aged, 80 and over, Genetics, 0303 health sciences, Mutation, NF-kappa B, High-Throughput Nucleotide Sequencing, hemic and immune systems, Genomics, Hematology, Middle Aged, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Female, Lymphoma, Large B-Cell, Diffuse, Signal Transduction, Adult, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Genetic Heterogeneity, 03 medical and health sciences, Internal medicine, medicine, Humans, Aged, 030304 developmental biology, Genome, Human, Genetic heterogeneity, Germinal center, Cancer, Cell Biology, CD79B, medicine.disease, Lymphoma, Gene expression profiling, 030104 developmental biology, Myeloid Differentiation Factor 88, Diffuse large B-cell lymphoma, 030215 immunology
Abstract

Introduction: MYD88 mutations, notably the recurrent gain-of-function L265P variant, are a distinguishing feature of Activated B-Cell like (ABC) Diffuse Large B Cell Lymphoma (DLBCL), leading to constitutive NFkB pathway activation. The frequency of MYD88 mutations in DLBCL and other hematologic malignancies is well described; however, there has not yet been a large-scale study of a MYD88 mutated patient cohort with additional Next Generation Sequencing (NGS), copy number variation (CNV), and gene expression data, in order to thoroughly characterize the associated genomic profiles of these patients. The aims of our study were to compare the L265P and non-L265P mutations in terms of pathological and genetic features, to better detail the genomic background associated with MYD88 mutations in order to delineate patients potentially sensitive to targeted therapies, and to define the prognostic value of MYD88 mutations according to different genomic contexts. Methods: A cohort of 361 DLBCL patients (94 MYD88 mutant and 267 MYD88 wild-type) was selected among the prospective, multicenter and randomized LNH-03B and LNH09-7B (NCT01195714) LYSA trials, as well as among patients sequenced at our institution as part of routine procedure. Cell of origin (COO) classification was obtained with HGU133+2.0 Affymetrix GeneChip arrays for 214 patients, with RT-MLPA for 77 patients1 and with Hans immunohistochemistry (IHC) method for 49 patients. All cases were submitted to next generation sequencing (NGS) focusing on 34 genes (Lymphopanel2) in order to analyze associated mutations and copy number variations (CNVs), as well as IHC, FISH, and clinical and prognostic analyses. Results: Importantly, we highlighted different genomic profiles for MYD88 L265P and MYD88 non-L265P mutant DLBCL, shedding light on their divergent backgrounds. Clustering analysis segregated subgroups according to associated genetic alterations among patients with either MYD88 L265P or non-L265P mutations. As such, clustering separated MYD88 L265P mutated DLBCL with associated PIM1 (52%), CD79B (52%), KMT2D (42%), and PRDM1 (32%) mutations, as well as MYD88 L265P mutated DLBCL with CDKN2A/B (67%/50%), PRDM1 (57%) and TNFAIP3 (52%) CNVs. We showed that associated CD79B and MYD88 L265P mutations act synergistically to increase NFkB pathway activation, although the majority of ABC MYD88 L265P mutant cases harbor downstream NFkB alterations, which can potentially predict BTK inhibitor resistance. Of note, although the MYD88 L265P variant was not an independent prognostic factor in ABC DLBCL, associated CD79B mutations significantly improved the survival of MYD88 L265P mutant ABC DLBCL in our cohort both in OS (p=0.02) and PFS (p=0.01), whereas the association of CARD11 or TNFAIP3 alterations did not impact survival. Interestingly, MYD88 mutant DLBCL cases were significantly more likely to experience central nervous system (CNS) relapse than MYD88 WT cases (p=0.02), as were MYD88 L265P mutant cases specifically (p=0.03). This result still tended toward statistical significance when considering only ABC patients (7 of 11 ABC CNS-relapsing cases were MYD88 mutant, p=0.1) but would have to be confirmed in a larger cohort. Conclusions: This study highlights the relative heterogeneity of MYD88 mutant DLBCBL, adding to the field's knowledge of the distinct genetic backgrounds of these subgroups. Our data highlights the theranostic and prognostic relevance of examining MYD88 and associated genomic alterations, emphasizing the usefulness of genomic profiling to best stratify patients for targeted therapy. 1. Mareschal S, Ruminy P, Bagacean C, et al. Accurate Classification of Germinal Center B-Cell-Like/Activated B-Cell-Like Diffuse Large B-Cell Lymphoma Using a Simple and Rapid Reverse Transcriptase-Multiplex Ligation-Dependent Probe Amplification Assay: A CALYM Study. The Journal of molecular diagnostics : JMD. 2015;17(3):273-283. 2. Dubois S, Viailly P-J, Mareschal S, et al. Next Generation Sequencing in Diffuse Large B Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016;22(12):2919-2928. Disclosures Salles: Novartis: Consultancy, Honoraria; Mundipharma: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding.

Published
2017

23. Integrated Analysis of IGHV Gene Status, Cell-of-Origin Signature and Genomic Features in Diffuse Large B-Cell Lymphoma

Author

Bettina Fabiani, Corinne Haioun, Pierre-Julien Viailly, André Marc, Philippe Bertrand, Elodie Bohers, Sydney Dubois, Jean-Philippe Jais, Hervé Tilly, Freda K. Stevenson, Thierry Jo Molina, Christiane Copie-Bergman, Martin Figeac, Gilles Salles, Bruno Tesson, Philippe Ruminy, Frederic Peyrade, Catherine Maingonnat, Fabrice Jardin, Jean-Michel Picquenot, Karen Leroy, Thierry Fest, Pascaline Etancelin, Nicolas Ketterer, Thierry Lamy, Pauline Peyrouze, Sylvain Mareschal, and Richard Delarue

Subjects
Oncology, Genetics, medicine.medical_specialty, Immunology, Somatic hypermutation, Germinal center, Cell Biology, Hematology, Biology, CD79B, medicine.disease, Biochemistry, GNA13, Lymphoma, Germline mutation, hemic and lymphatic diseases, Internal medicine, medicine, IGHV@, Diffuse large B-cell lymphoma
Abstract

The molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) has been highlighted by gene expression profiling (GEP), dividing DLBCL into the following three main molecular subtypes with different clinical outcomes and responses to immunochemotherapy: the germinal center B-cell-like (GCB) subtype, the activated B-cell-like (ABC) subtype and the primary mediastinal B-cell lymphoma (PMBL) subtype. Despite frequent translocations involving the IGH (heavy chain) locus, B-cell receptor (BCR) expression is retained in almost all DLBCL, indicating that BCR signaling is crucial for the survival of malignant cells. Furthermore, DLBCL are characterized by recurrent somatic mutations that are supposed to be oncogenic drivers. Here, with the aim to more accurately define the DLBCL pathogenic subgroups, we report a detailed immunogenetic analysis of IGH rearrangements in a well-defined GEP DLBCL cohort and correlate these features with the somatic mutation status of recurrently mutated genes involved in lymphomagenesis. Methods: 204 DLBCL enrolled in the prospective LYSA LNH03 trial program were classified into molecular subtypes by GEP using Affymetrix arrays [82 ABC (40.2%), 77 GCB (37.7%), 29 (14.2%) unclassified and 16 PMBL (7.8%)]. The amplification of complete VDJ rearrangements was realized using BIOMED-2 protocols. Somatic hypermutation (SHM) characteristics were studied (mutation rate, glycosylation N-X-S/T sites, RGYW hotspots, composition of CDR3) and correlated with the molecular subtypes. To obtain a more comprehensive molecular portrait of the DLBCL cases, GEP and IGH VDJ analyses were correlated with the mutational status of a panel of 34 recurrently mutated genes in DLBCL such as MYD88, EZH2, CD79B, TNFAIP3, CARD11 and GNA13 (Dubois et al. Clinical Cancer Research 2016). Results: A total of 153/204 (75%) clonal VDJ rearrangements were successfully determined. Failures to detect clonotypic sequences were predominantly seen in PMBL (56%) and unclassified (31%) cases. The ABC subtype display a significantly lower SHM rate than the 3 other subtypes, especially in contrast to the PMBL subgroup that was characterized by a higher SHM rate (p Disclosures Haioun: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Salles:Mundipharma: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding.

Published
2016

24. Genetic polymorphisms in ARID5B, CEBPE, IKZF1 and CDKN2A in relation with risk of acute lymphoblastic leukaemia in adults: a Group for Research on Adult Acute Lymphoblastic Leukaemia (GRAALL) study

Author

Eric Delabesse, Xavier Thomas, Véronique Lhéritier, Nicolas Pottier, Jean-Yves Cahn, Elizabeth Macintyre, Soizic Guihard, Nathalie Grardel, Meyling Cheok, Arnaud Pigneux, Céline Berthon, Hervé Dombret, Norbert Ifrah, Pauline Peyrouze, Marie C. Béné, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Service d'Immunologie [CHRU Nancy], Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Impact de l'Environnement Chimique sur la Santé Humain, PRES Université Lille Nord de France, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hospices Civils de Lyon ( HCL ), IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne-Université Paris 13 ( UP13 ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne

Subjects
Male, MESH : Transcription Factors, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: CCAAT-Enhancer-Binding Proteins, 0302 clinical medicine, CDKN2A, MESH : Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH : Female, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Hematology, MESH: Transcription Factors, MESH: Ikaros Transcription Factor, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH : Adult, 3. Good health, DNA-Binding Proteins, MESH : CCAAT-Enhancer-Binding Proteins, MESH: Young Adult, 030220 oncology & carcinogenesis, Female, MESH : DNA-Binding Proteins, Adult, MESH : Male, MESH : Young Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Ikaros Transcription Factor, Young Adult, MESH : Ikaros Transcription Factor, Humans, Genetic Predisposition to Disease, MESH : Middle Aged, 030304 developmental biology, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, MESH : Humans, MESH: Adult, CEBPE, MESH: Male, Immunology, CCAAT-Enhancer-Binding Proteins, Lymphoblastic leukaemia, MESH : Genetic Predisposition to Disease, MESH: Female, MESH: DNA-Binding Proteins, Transcription Factors
Abstract

International audience

Published
2012

25. Integrative Analysis of Diffuse Large B Cell Lymphoma Mutational Landscape: A Lysa Study

Author

Elodie Bohers, Thierry Jo Molina, Philippe Bertrand, Bertrand Coiffier, Jean-Philippe Jais, Christiane Copie-Bergman, Philippe Ruminy, Gilles Salles, Frederic Peyrade, Nicolas Ketterer, Corinne Haioun, Pierre-Julien Viailly, Karen Leroy, Thierry Lamy, Hervé Tilly, Pauline Peyrouze, Sydney Dubois, Sylvain Mareschal, Tony Petrella, Marc André, Richard Delarue, Bettina Fabiani, Bruno Tesson, Josette Brière, André Bosly, Danielle Canioni, Thierry Fest, Fabienne Desmots, Catherine Maingonnat, Martin Figeac, and Fabrice Jardin

Subjects
Tumor necrosis factors, Human leukocyte interferon, Immunology, Tumor Necrosis Factor alpha-Induced Protein 3, Cell Biology, Hematology, Biology, Bioinformatics, medicine.disease, NFKB1, Biochemistry, Lymphoma, Gene expression profiling, hemic and lymphatic diseases, Cancer research, medicine, Diffuse large B-cell lymphoma
Abstract

Introduction Diffuse Large B Cell Lymphoma (DLBCL) is the most common lymphoid malignancy, accounting for 30-40% of all Non Hodgkin Lymphomas. Gene expression profiling (GEP) has identified three main subtypes of DLBCL: Germinal Center B-cell like (GCB), Activated B-Cell like (ABC) and Primary Mediastinal B-cell Lymphoma (PMBL). Recently, Next Generation Sequencing (NGS) has enabled a more detailed characterization of DLBCL mutational profiles. Conventional techniques such as immunohistochemistry (IHC) and FISH are also widely used to describe DLBCL. However, no study has yet performed an integrative analysis of the mutational, gene expression, IHC and FISH profiles of DLBCL, in order to provide a comprehensive view of this disease. Methods 215 patients with de novo DLBCL in the prospective, multicenter and randomized LNH-03B clinical trials led by the LYmphoma Study Association (LYSA) were included in this study. Microarray-based GEP identified 81 ABC, 83 GCB, 18 PMBL and 33 other. Mutational profiles of patients' tumor DNA were established using Lymphopanel NGS, designed to identify mutations in 34 genes important for lymphomagenesis. For each recurrently mutated gene, we applied ROMER (Ritchie, Nucleic Acids Res, 2015) to perform gene set enrichment analysis on differential expression profiles of mutant and wild-type patients, using a multifactorial model accounting for subtype. The gene sets were obtained from the MSIGDB Hallmarks (Subramanian A, PNAS, 2005) and Signaturedb (Schaffer, Immunol Rev, 2006) collections. When possible, IHC was performed for IgM (n=150), MYC (n=140), BCL2 (n=148), BCL6 (n=146), CD10 (n=152), FOXP1 (n=147) and MUM1 (n=152); FISH was performed for MYC (n=131), BCL2 (n=133) and BCL6 (n=131). Results As expected, EZH2 mutations were significantly associated with upregulation of GCB gene expression (p An association between BCL6 translocations and ABC subtype was confirmed, via a correlation with ABC-enriched CD79B mutations (p=0.02), although interestingly not with MYD88 mutations. MYD88 mutations were correlated with an upregulation of genes involved in proliferation or repressed by PRDM1 (FDR=0.04 each), as well as with an upregulation of genes involved in checkpoint controls, such as E2F targets and genes involved in DNA repair (FDR=0.03 each). All MYD88 mutants expressed FOXP1 in IHC (p PMBL-enriched mutations in our cohort were frequently associated with IgM and FoxP1 negative IHC, as expected (WHO 2008 and Roschewski, Nat Rev Clin Onc). XPO1 and ITPKB mutations were correlated with JAK-STAT pathway activation in the total cohort, including upregulation of interferon-inducible genes for both gene mutations (FDR=0.02 and FDR=0.08 respectively) and upregulation of BCL6-repressed genes for XPO1 mutations only (FDR=0.02). Interestingly, CD58 mutations were significantly correlated with upregulation of Nfkb pathway target genes (FDR=0.06), perhaps due to their negative impact on CD2 activation and ROS production inhibition. Conclusion The results herein provide steps toward a comprehensive, multi-level overview of DLBCL. We highlight differential gene set expression linked to gene mutation status, as well as driver translocation-associated mutational profiles. By using an integrative analysis approach, this study broadens our understanding of DLBCL subtypes' diverse genetic backgrounds. Disclosures Briere: St. Louis Hospital, Paris, France: Employment. Salles:Celgene Corporation; Roche: Speakers Bureau; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding.

Published
2015

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