TY - JOUR
T1 - Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma
T2 - prognostic significance of E2F-1 and p16INK4A
AU - Møller, M B
AU - Kania, Per Walter
AU - Ino, Y
AU - Gerdes, A M
AU - Nielsen, O
AU - Louis, D N
AU - Skjødt, K
AU - Pedersen, N T
PY - 2000/5
Y1 - 2000/5
N2 - 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.
AB - 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.
KW - Antigens, Nuclear
KW - Carrier Proteins
KW - Cell Cycle Proteins
KW - Chromosome Aberrations
KW - Cyclin D1
KW - Cyclin D3
KW - Cyclin-Dependent Kinase 4
KW - Cyclin-Dependent Kinase Inhibitor p16
KW - Cyclin-Dependent Kinases
KW - Cyclins
KW - DNA-Binding Proteins
KW - Databases as Topic
KW - E2F Transcription Factors
KW - E2F1 Transcription Factor
KW - Female
KW - Genes, Retinoblastoma
KW - Genes, p53
KW - Humans
KW - Loss of Heterozygosity
KW - Lymphoma, B-Cell
KW - Lymphoma, Large B-Cell, Diffuse
KW - Male
KW - Middle Aged
KW - Neoplasm Staging
KW - Nuclear Proteins
KW - Polymorphism, Single-Stranded Conformational
KW - Predictive Value of Tests
KW - Prognosis
KW - Proto-Oncogene Proteins
KW - Proto-Oncogene Proteins c-mdm2
KW - Proto-Oncogenes
KW - Retinoblastoma-Binding Protein 1
KW - Survival Analysis
KW - Transcription Factor DP1
KW - Transcription Factors
U2 - 10.1038/sj.leu.2401761
DO - 10.1038/sj.leu.2401761
M3 - Journal article
C2 - 10803523
SN - 0887-6924
VL - 14
SP - 898
EP - 904
JO - Leukemia
JF - Leukemia
IS - 5
ER -