Aberrant p15, p16, p53, and DAPK Gene Methylation in Myelomagenesis: Clinical and Prognostic Implications

作者：Geraldes Catarina^*; Goncalves Ana Cristina; Cortesao Emilia; Pereira Marta Isabel; Roque Adriana; Paiva Artur; Ribeiro Leticia; Nascimento Costa Jose Manuel; Sarmento Ribeiro Ana Bela

来源：Clinical Lymphoma Myeloma & Leukemia, 2016, 16(12): 713-+.

DOI：10.1016/j.clml.2016.08.016

• Epigenetic modifications
• Gene expression
• Monoclonal gammopathies
• Pathogenesis
• Tumor suppressor genes

Aberrant DNA methylation is important in multiple myeloma pathogenesis. Methylation of p15, p16, p53, and DAPK genes was evaluated in bone marrow (94 patients; 8 controls) by methylation-specific polymerase chain reaction; 63% of patients with multiple myeloma and 39% of patients with monoclonal gammopathy of uncertain significance presented >= 1 hypermethylated gene (P < .05). This supports a relevant role for hypermethylation in the pathogenesis of the plasma cell neoplasms.
Background: Aberrant DNA methylation is considered a crucial mechanism in the pathogenesis of monoclonal gammopathies. We aimed to investigate the contribution of hypermethylation of 4 tumor suppressor genes to the multistep process of myelomagenesis. Methods: The methylation status of p15, p16, p53, and DAPK genes was evaluated in bone marrow samples from 94 patients at diagnosis: monoclonal gammopathy of uncertain significance (MGUS) (n = 48), smoldering multiple myeloma (SMM) (n = 8) and symptomatic multiple myeloma (MM) (n = 38), and from 8 healthy controls by methylation-specific polymerase chain reaction analysis. Results: Overall, 63% of patients with MM and 39% of patients with MGUS presented at least 1 hypermethylated gene (P < .05). No aberrant methylation was detected in normal bone marrow. The frequency of methylation for individual genes in patients with MGUS, SMM, and MM was p15, 15%, 50%, 21%; p16, 15%, 13%, 32%; p53, 2%, 12,5%, 5%, and DAPK, 19%, 25%, 39%, respectively (P < .05). No correlation was found between aberrant methylation and immunophenotypic markers, cytogenetic features, progression-free survival, and overall survival in patients with MM. Conclusions: The current study supports a relevant role for p15, p16, and DAPK hypermethylation in the genesis of the plasma cell neoplasm. DAPK hypermethylation also might be an important step in the progression from MGUS to MM.

• 出版日期2016-12