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Concurrent disruption of p16INK4a and the ARF-p53 pathway predicts poor prognosis in aggressive non-Hodgkin's lymphoma

Leukemia volume 14, pages 1727–1735 (2000)Cite this article

Abstract

The INK4a/ARF locus at chromosome 9p21 encodes two structurally and functionally distinct molecules with tumor-suppressive properties. p16INK4a controls cell cycle progression by inhibiting phosphorylation of the retinoblastoma protein (Rb), while ARF prevents MDM2-mediated degradation of p53. By using a panel of PCR-based methods, we have examined the status of the p16INK4a, ARF and p53 genes in 123 cases of non-Hodgkin's lymphoma (NHL) at diagnosis. Alterations of one or more of these genes were detected in seven of 36 (19%) cases with low- to intermediate-grade histology, and in 35 of 87 (40%) cases with aggressive histology. For the aggressive lymphomas, the Kaplan–Meier estimate of overall survival for cases with disruption of either p16INK4a or the ARF-p53 pathway was not different from cases with retention of both pathways (5-year survival 45% vs 35%; P = 0.85), suggesting that selective inactivation of one of the pathways does not significantly influence overall survival. By contrast, the 5-year survival was only 7% for cases with concurrent disruption of p16INK4a and the ARF-p53 pathway vs 38% for cases with retention of one or both pathways (P = 0.005). Similar results were obtained when the analysis was confined to diffuse large B cell lymphomas (P = 0.019). On stepwise multivariate regression analysis including factors from the international prognostic index, concurrent disruption of p16INK4a and the ARF-p53 pathway was an independent negative prognostic factor in NHL with aggressive histology (P = 0.006). Our results suggest that the compound status of the p16INK4a and ARF-p53 pathways is a major determinant of outcome in NHL.

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Acknowledgements

This study was supported by grants from the Danish Cancer Society, the E Danielsen Foundation, the Kaarsen Foundation, the Danish Medical Research Council, the Danish Cancer Research Foundation, and the Novo Nordisk Foundation.

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Authors and Affiliations

  1. Department of Tumor Cell Biology, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark

    K Grønbæk, T Nedergaard, J Zeuthen & P Guldberg

  2. Department of Pathology, Herlev Hospital, Copenhagen, Denmark

    K Grønbæk, E Ralfkiaer & P Møller

  3. Department of Hematology, Rigshospitalet, Copenhagen, Denmark

    P de Nully Brown

  4. Department of Pathology, Odense University Hospital, Denmark

    MB Møller

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Grønbæk, K., de Nully Brown, P., Møller, M. et al. Concurrent disruption of p16INK4a and the ARF-p53 pathway predicts poor prognosis in aggressive non-Hodgkin's lymphoma. Leukemia 14, 1727–1735 (2000). https://doi.org/10.1038/sj.leu.2401901

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