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Lymphoma

Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A

Leukemia volume 14, pages 898–904 (2000)Cite this article

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 novoDLCLs 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 p16INK4Ainactivation (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.

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Acknowledgements

We thank Jan Alsner for kindly providing DNA from retinoblastoma patients with known RB1 mutations. We also appreciate the excellent technical assistance of Marianne Christensen, Maj-Britt S Berg, Lene Nielsen and Bodil Harder. The work was supported in part by the Danish Medical Research Council Grant 9400660.

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Authors and Affiliations

  1. Department of Pathology, University of Southern Denmark – Odense University, Denmark

    MB Møller, PW Kania, O Nielsen & NT Pedersen

  2. Department of Pathology (Neuropathology) and Neurosurgical Service, Molecular Neuro-Oncology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Y Ino & DN Louis

  3. Department of Clinical Genetics, University of Southern Denmark – Odense University, Denmark

    A-M Gerdes

  4. Department of Immunology and Microbiology, University of Southern Denmark – Odense University, Denmark

    K Skjødt

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  1. MB Møller
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Møller, M., Kania, P., Ino, Y. et al. Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A. Leukemia 14, 898–904 (2000). https://doi.org/10.1038/sj.leu.2401761

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