title: Several mechanisms lead to the inactivation of the CDKN2A (P16), P14ARF, or CDKN2B (P15) genes in the GCB and ABC molecular DLBCL subtypes.
abstract: Diffuse large B-cell lymphoma (DLBCL) represents the most frequent type of aggressive lymphoma. Deletions of the CDKN2A locus, encoding the proteins CDKN2A (P16), P14ARF, and of the CDKN2B locus, encoding the protein CDKN2B (P15), affect one-third of DLBCL patients. Although other mechanisms that decrease gene expression have been reported, such as promoter methylation, the prognostic value of these mechanisms is still unclear. We studied the deletion and methylation status of these genes in 171 patients and correlated the genomic results with their mRNA expression level and clinical outcome. CDKN2A, P14ARF, and CDKN2B deletions were significantly correlated with decreased mRNA expression (P<0.0001, P<0.0001, and P=0.0148, respectively). P14ARF was methylated in only two patients (1.3%), whereas CDKN2A and CDKN2B were methylated in 36.7 and 31.4% of patients, respectively. Methylation levels greater than 25% were associated with decreased expression of CDKN2A (P=0.0169). CDKN2A and CDKN2B inactivation by deletion or methylation was observed in 42.7 and 37.4% of cases, respectively. Including P14ARF deletions, we identified an inactivating mechanism for at least one of these genes in 47% of patients. Although gene inactivation was not correlated with the international prognostic index, P14ARF and CDKN2B inactivation was significantly associated with shorter survival (P=0.0048 and P=0.0413, respectively), whereas CDKN2A was not (P=0.085). Low mRNA expression levels of these genes were correlated with the ABC phenotype. Furthermore, our results show that an inactivating methylation was more frequent in the GCB phenotype.
authors.affiliation: INSERM U918, Groupe d'étude des Proliférations Lymphooedes, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23 (IFRMP23), Rouen, France.
authors.forename: Suzan
authors.initials: S
authors.lastname: Guney
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jardin
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertrand
authors.forename: Sylvain
authors.initials: S
authors.lastname: Mareschal
authors.forename: Françoise
authors.initials: F
authors.lastname: Parmentier
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Picquenot
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.forename: Christian
authors.initials: C
authors.lastname: Bastard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D018628:Gene Dosage; D020868:Gene Silencing; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D015996:Survival Rate; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*; D055815:Young Adult
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF