p16/INK4a gene inactivation by hypermethylation is associated with aggressive variants of monoclonal gammopathies

Introduction: A model of a stepwise malignant transformation has been proposed for the pathogenesis of monoclonal gammopathies. In this model, cell cycle regulators play a central role as a source of genetic events; particulary, p16/INK4a gene acts as a tumoral suppressor gene and, recently, inactivation of this gene through a methylation mechanism, has been observed in multiple myeloma patients. Under the diagnosis of monoclonal gammopathies there is a broad spectrum of disorders with very diAerent outcomes, ranging from indolent courses, such as those of monoclonal gammopathy of undetermined significance, Waldestron macroglobulinemia and smoldering multiple myeloma, to aggressive diseases such as symptomatic MM and primary plasma cell leukemia. To the best of our knowledge, the activity of p16 gene has not been evaluated and compared in these diAerent subtypes of monoclonal gammopathies. Materials and methods: The methylation status of the p16 gene was analysed in a group of 159 patients with monoclonal gammopathies (40 monoclonal gammopathy of uncertain significance, eight Waldenstrom Macroglobulinemia, eight smoldering multiple myeloma, 98 symptomatic multiple myeloma and five primary plasma cell leukemia) using three diAerent assays (restriction enzymes and PCR or S-B and modification by sodium bisulphite). Results: Forty-one of 98 MM patients (41.8%) as well as four of the five (80%) primary PCL patients showed methylation of the p16 gene, while none of the patients with monoclonal gammopathy of undetermined significance, Waldenstrom Macroglobulinemia or smoldering multiple myeloma displayed a methylation status. Conclusion: These findings suggest that the methylation of the p16 gene could be a relevant oncogenic event in the monoclonal gammopathies evolution being associated with the most aggressive forms. The Hematology Journal (2001) 2, 146-149