Concurrent disruption of p16(INK4a) and the ARF-p53 pathway predicts poor prognosis in aggressive non-Hodgkin's lymphoma

The INK4a/ARF locus at chromosome 9p21 encodes two structurally and functio nally distinct molecules with tumor-suppressive properties. p16(INK4a) cont rols cell cycle progression by inhibiting phosphorylation of the retinoblas toma 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 p16( INK4a), ARF and p53 genes in 123 cases of non-Hodgkin's lymphoma (NHL) at d iagnosis. 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 8 7 (40%) cases with aggressive histology. For the aggressive lymphomas, the Kaplan-Meier estimate of overall survival for cases with disruption of eith er p16(INK4a) Or the ARF-p53 pathway was not different from cases with rete ntion of both pathways (5-year survival 45% vs 35%; P = 0.85), suggesting t hat selective inactivation of one of the pathways does not significantly in fluence overall survival. By contrast, the 5-year survival was only 7% for cases with concurrent disruption of p16(INK4a) and the ARF-p53 pathway vs 3 8% for cases with retention of one or both pathways (P = 0.005). Similar re sults were obtained when the analysis was confined to diffuse large B cell lymphomas (P = 0.019). On stepwise multivariate regression analysis includi ng factors from the international prognostic index, concurrent disruption o f p16(INK4a) and the ARF-p53 pathway was an independent negative prognostic factor in NHL with aggressive histology (P = 0.006). Our results suggest t hat the compound status of the p16(INK4a) and ARF-p53 pathways is a major d eterminant of outcome in NHL.