HMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

Abstract

Monoclonal gammopathies are a group of disorders characterized by clonal proliferation and accumulation of immunoglobulin-producing plasma cells. Multiple myeloma and monoclonal gammopathy of undetermined significance are the most common monoclonal gammopathies; the two comprise a spectrum of disorders, ranging from a relatively benign disease, monoclonal gammopathy of undetermined significance, to a malignant disease, multiple myeloma. Aberrant promoter methylation represents a primary mechanism of gene silencing during tumorigenesis. DNA repair systems act to maintain genome integrity in the presence of replication errors, environmental insults, and the cumulative effects of aging. The methylation patterns of two genes implicated in DNA repair, O6 methylguanine DNA methyl-transferase (MGMT) and human mutL homologue1 (hMLH1) have been detected in various solid tumours. With the purpose of studying the gene silencing of MGMT and hMLH1 in plasma cell disorders, we investigated the methylation status and expression of both genes in: 29 cases of multiple myeloma; one case of plasma cell leukaemia; 13 cases of monoclonal gammopathy of undetermined significance; and two cases of polyclonal plasmacytosis, using methylation-specific polymerase-chain reaction and immunohistochemical techniques. Methylation frequencies for MGMT were 23% in multiple myeloma and 8% in monoclonal gammopathy of undetermined significance. It was 10% for hMLH1 in multiple myeloma. None of the patients diagnosed with monoclonal gammopathy of undetermined significance had hMLH1 hypermethylated. In addition, 50% of myeloma cases had a loss of hMLH1 expression, whereas silencing of MGMT was observed in 43% of myeloma and 36% of samples with monoclonal gammopathy of undetermined significance. This study indicates that repair pathway defects play a role in the pathogenesis and evolution of monoclonal gammopathies, and suggests that inactivation of hMLH1 could be implicated in multiple myeloma tumorigenesis.