Homozygous deletion of INK4a/ARF genes and overexpression of bcl-2 in relation with poor prognosis in immunocompetent patients with primary central nervous system lymphoma of the diffuse large B-cell type

Only a few reports have been published on molecular genetic alterations in primary central nervous system lymphomas (PCNSLs) of the diffuse large B-ce ll type and no reports have addressed the correlation between the genetic a lterations and clinical course of the patients with this neoplasm. Thus, th e molecular background of the PCNSL and its importance for the clinical cou rse of the patients are still unclear. We investigated a series of 14 patie nts with PCNSL to determine structural alterations of the INK4a/ARF, MDM2, and TP53 genes, the status of bcl-2 and bcl-6 protein expression, and the c linical course of the patients (i.e. their survival time after diagnosis). No structural alterations of MDM2 and TP53 genes were found. Only INK4a/ARF genes whose expression affects both the p16INK4a-Rb and p14ARF-mdm2-p53 pa thways in the regulation for cell cycle and apoptosis, showed an alteration of the homozygous deletions at a high frequency (nine of 14 patients: 64%) . This specific alteration was not related with the bcl-6 expression, but a relation was shown with overexpression of the bcl-2 anti-apoptotic protein (p = 0.036, chi-square test), as well as a shorter patient survival (p = 0 .044, Wilcoxon test). There was only a tendency, not a significant correlat ion, in which the patients with bcl-2 overexpression resulted in poor progn osis (p = 0.149). The present study is the first to suggest that the INK4a/ ARF gene homozygous deletions and overexpression of the bcl-2 protein may b e correlated with each other and together serve as important predictors for the prognosis of patients with PCNSL.