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 methylationspecific 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.

DNA repair pathways in human multiple myeloma

“…In a study of 30 patients with MM and 13 with MGUS, MLH1 promoter was found methylated in plasma cells of 10% of patients with MM but not from MGUS patients. 108 MLH1 promoter methylation was also associated with a decrease or loss of MLH1 gene expression in MMCs. These data suggest that a decrease in MLH1 expression follows promoter hypermethylation, and may play a role in the transition of MGUS to MM.…”

O6-Methylguanine-DNA methyltransferase protein expression by immunohistochemistry in brain and non-brain systemic tumours: systematic review and meta-analysis of correlation with methylation-specific polymerase chain reaction

“…Characteristics of non-glioma studies included in the analysis [1,32,63-67,69,70,72-75,77-83,91,95,96,128-139]. …”

DNA methylation alterations in multiple myeloma as a model for epigenetic changes in cancer

“…O6‐methylguanine DNA methyltransferase (MGMT) and human mutL homolog 1 (hMLH1), both important in DNA repair, have been shown to be methylated with increased frequency in MM patients when compared to MGUS (Table 2). 79 This may be an important link in our understanding of myeloma pathogenesis but more clinical data on the prevalence of DNA damage repair genes in MM is needed.…”