Hypermethylation of p16INK4A gene promoter during the progression of plasma cell dyscrasia

Recent studies have indicated a close relationship between inactivation of tumor suppressor genes (TSGs) and disease progression. The genes encoding the cyclin-dependent kinase inhibitors p16(INK4A) and p15(INK4B) are potent TSGs, and correlations between their inactivation and disease progression have also been reported in various malignancies. In this study, we analyzed the methylation status of p16(INK4A) and p15(INK4B) gene promoters in plasma cell dyscrasias (PCDs) by methylation-specific PCR (MSP), In analyses using DNAs extracted from bone marrow mononuclear cells (BM-MNCs), patients with multiple myeloma (MM) showed frequent hypermethylation of the p16(INK4A) gene (15/37, 41%), whereas p15(INK4B) gene methylation was not so frequent (5/37, 14%), Many patients whose BM-MNC showed dense methylation of the p16(INK4A) gene had extramedullary plasmacytoma (extra-PC), and all available extra-PC samples showed alterations of the p16(INK4A) gene (4; dense methylation, 1; homozygous deletion). In contrast to MM, hypermethylation of the p16(INK4A) gene was significantly infrequent in indolent PCDs (2/22, 9%, P = 0.0055), The infrequency in indolent PCDs was also confirmed by analyses using DNAs extracted from BM smears (1/29, 3%). It is possible that hypermethylation of the p16(INK4A) gene promoter contributes to progression to aggressive MM from indolent PCD, especially to extra-PC development.