title: Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A.
abstract: In the present study, we analysed 34 de novo diffuse large B cell lymphoma (DLCL) from a population-based lymphoma registry for alterations of the RB1 pathway at the genetic (RB1 and CDK4) and protein (pRb, cyclin D1, cyclin D3, CDK4, and E2F-1) level. The results were correlated with the data from our previous studies of CDKN2A deletion and hypermethylation, other p53 pathway components, p27Kip1 expression, and proliferation, as well as with clinical outcome, including prognosis. We found aberrant pRb expression in four (12%) of 34 DLCLs. One of these had a point mutation in intron 3 10 bp downstream of exon 3 generating a novel splice signal. Seven tumours (21%) showed cyclin D3 overexpression, including all three thyroid lymphomas (P = 0.006). Cyclin D3 overexpression and p16INK4A/pRb aberrations were mutually exclusive, supporting an oncogenic role for cyclin D3 in DLCL. p16INK4A inactivation, cyclin D3 overexpression, or aberrant pRb expression was identified in 18 of 34 DLCLs (53%). Combining these results with our previous p53 pathway studies showed that 82% of the de novo DLCLs had alterations of these pathways, and that both pathways were altered in 13 cases (38%). Low E2F-1 expression was associated with treatment failure (P = 0.020), and multivariate analysis of overall survival identified both low E2F-1 expression (relative risk = 6.9; P = 0.0037) and p16INK4A inactivation (relative risk = 3.3; P = 0.0247) as independent prognostic markers. These data support a role of E2F-1 as tumour suppressor gene in lymphoma and strongly suggest that the RB1 and p53 pathways are important in the development of de novo DLCL. Furthermore, low E2F-1 expression and p16INK4A inactivation may serve as prognostic markers for patients with this type of lymphoma.
authors.affiliation: Department of Pathology, University of Southern Denmark-Odense University.
authors.forename: M B
authors.initials: MB
authors.lastname: Møller
authors.forename: P W
authors.initials: PW
authors.lastname: Kania
authors.forename: Y
authors.initials: Y
authors.lastname: Ino
authors.forename: A M
authors.initials: AM
authors.lastname: Gerdes
authors.forename: O
authors.initials: O
authors.lastname: Nielsen
authors.forename: D N
authors.initials: DN
authors.lastname: Louis
authors.forename: K
authors.initials: K
authors.lastname: Skjødt
authors.forename: N T
authors.initials: NT
authors.lastname: Pedersen
mesh_terms: D034961:Antigens, Nuclear; D002352:Carrier Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002869:Chromosome Aberrations; D019938:Cyclin D1 / Q000235:genetics; D056743:Cyclin D3; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D016213:Cyclins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D019992:Databases as Topic; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005260:Female; D016161:Genes, Retinoblastoma; D016158:Genes, p53; D006801:Humans; D019656:Loss of Heterozygosity; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D011519:Proto-Oncogenes; D056465:Retinoblastoma-Binding Protein 1; D016019:Survival Analysis; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D034961:Antigens, Nuclear; C534696:CCND3 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D019938:Cyclin D1; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases