title: Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R-CHOP treatment: a GELA study.
abstract: Genomic alterations play a crucial role in the development and progression of diffuse large B-cell lymphomas (DLBCLs). We determined gene copy number alterations (GCNAs) of TP53, CDKN2A, CDKN1B, BCL2, MYC, REL, and RB1 with a single polymerase chain reaction (PCR) assay (quantitative multiplex PCR of short fragments [QMPSF]) in a cohort of 114 patients with DLBCL to assess their prognostic value and relationship with the gene expression profile. Losses of TP53 and CDKN2A, observed in 8% and 35% of patients, respectively, were significantly associated with a shorter survival after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment, independently of the International Prognostic Index and of the cell of origin. Analysis of the 9p21 genomic region indicated that transcripts encoding p14ARF and p16INK4A were both disrupted in most patients with CDKN2A deletion. These patients predominantly had an activated B-cell profile and showed a specific gene expression signature, characterized by dysregulation of the RB/E2F pathway, activation of cellular metabolism, and decreased immune and inflammatory responses. These features may constitute the molecular basis sustaining the unfavorable outcome and chemoresistance of this DLBCL subgroup. Detection of TP53 and CDKN2A loss by QMPSF is a powerful tool that could be used for patient stratification in future clinical trials.
authors.affiliation: Service d'Hématologie and INSERM UMR918, Centre Henri Becquerel, University of Rouen, Rue d'Amiens, Rouen, France. fjardin@rouen.fnclcc.fr
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jardin
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Jais
authors.forename: Thierry-Jo
authors.initials: TJ
authors.lastname: Molina
authors.forename: Françoise
authors.initials: F
authors.lastname: Parmentier
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Picquenot
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruminy
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.forename: Christian
authors.initials: C
authors.lastname: Bastard
authors.forename: Gilles-André
authors.initials: GA
authors.lastname: Salles
authors.forename: Pierre
authors.initials: P
authors.lastname: Feugier
authors.forename: Catherine
authors.initials: C
authors.lastname: Thieblemont
authors.forename: Christian
authors.initials: C
authors.lastname: Gisselbrecht
authors.forename: Aurelien
authors.initials: A
authors.lastname: de Reynies
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coiffier
authors.forename: Corinne
authors.initials: C
authors.lastname: Haioun
authors.forename: Karen
authors.initials: K
authors.lastname: Leroy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D000069283:Rituximab; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014750:Vincristine / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D019941:Cyclin-Dependent Kinase Inhibitor p16; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D020569:Proto-Oncogene Proteins c-rel; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone