DNA methylation changes in multiple myeloma

Abstract

Using a candidate gene approach, we analyzed the methylation status of the promoter-associated CpG islands of 11 wellcharacterized tumor suppressor genes by methylation-specific polymerase chain reaction in five multiple myeloma (MM) cell lines and 56 patients with malignant plasma cell disorders. The frequency of aberrant methylation among the patient samples was 46.4% for SOCS-1, 35.7% for p16, 21.4% for E-cadherin, 12.5% for DAP kinase and p73, 1.8% for p15, MGMT as well as RARb, and 0% for TIMP-3, RASSF1A and hMLH1. We found at least one hypermethylated gene in 80.4% of the primary patient samples, while 33.9% harbored two or more hypermethylated genes. For the first time, we show that p73 may be hypermethylated in MM and thus be involved in the pathogenesis of plasma cell disorders. Hypermethylation of p16 at diagnosis was associated with a poorer prognosis. In patients with plasma cell leukemia, we found frequent simultaneous hypermethylation of p16, E-cadherin and DAP kinase. We conclude that aberrant methylation of tumor suppressor genes is a common event in malignant plasma cell disorders and that there is a correlation between methylation patterns and clinical characteristics in MM patients.

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

“…The difference in our results, compared with this study, may be accounted for the use of nonenriched plasma cells for the methylation-specific PCR technique; hence, Galm et al 35 probably would have underestimated the true frequency of this epigenetic event. Nevertheless, our findings support the work of Kotoula et al, 36 who described low expression or absence of hMLH1 in multiple myeloma samples with extensive bone marrow infiltration using a multiplex RT-PCR technique; they suggested that a deficiency of hMLH1 confers an unfavourable prognosis for multiple myeloma.…”

“…Hypermethylation of MGMT was observed in seven cases of multiple myeloma (including one case of plasma cell leukaemia) while only one monoclonal gammopathy of undetermined significance sample showed methylation. The frequency of MGMT methylation was higher in our series, compared to other studies: Galm et al 35 (1.8% in multiple myeloma); Seidl et al 37 (7% in myeloma and 4% in monoclonal gammopathy of undetermined significance); Rossi et al 38 (12.5% in multiple myeloma); and Chim et al 39 (0% in multiple myeloma). Once more, this discrepancy may be attributed to the use in those studies of not-purified plasma cells.…”

“…To our knowledge, there is only one study that analyses hMLH1 methylation in plasma cell dyscrasias 35 and did not find methylation of this gene in their cases. The difference in our results, compared with this study, may be accounted for the use of nonenriched plasma cells for the methylation-specific PCR technique; hence, Galm et al 35 probably would have underestimated the true frequency of this epigenetic event.…”

The role of p73 in hematological malignancies

“…Although no methylation of P73 gene was detected in all 13 MM patients, 65 another group reported P73 hypermethylation in 40% MM cell lines and in 12.5% MM patients examined (Table 1). 73 Finally, in a larger study on 142 patients with MM or MGUS, P73 methylation was detected in 15 and 21% of them, respectively. 74 Thus, silencing of P73 gene by its methylation is markedly associated also with MG.…”

p21WAF1/CIP1 induction by 5-azacytosine nucleosides requires DNA damage

“…DNA methylation is catalysed by DNA methyltransferases (DNMTs), which transfer the methyl moiety from the methyl donor S-adenosyl-methionine to the 5 position on the cytosine ring. Pharmacologic inhibition of DNMT in cancer cells causes reversal of promoter methylation associated with transcriptional activation of methylated tumor suppressor genes including p16, p15 and p73 (Galm et al, 2004). DNMT1 interacts directly with HDAC 1 and 2 as well as the histone methyltransferase SUV39H1 (Vaute et al, 2002).…”