DNA-methylation analysis identifies the E-cadherin gene as a potential marker of disease progression in patients with monoclonal gammopathies.
BACKGROUND
Silencing of tumor suppressor genes (TSG) by aberrant methylation (referred to as methylation) contributes to the pathogenesis of various human malignancies. However, little is known about the methylation of known and putative TSGs in monoclonal gammopathies. Thus, the authors investigated the methylation frequencies of 10 genes in patients with monoclonal gammopathies.


METHODS
The methylation patterns of the genes p16(INK4a) (p16), tissue inhibitor of metalloproteinase 3 (TIMP3), p15(INK4b) (p15), E-cadherin (ECAD), death-associated protein kinase (DAPK), p73, RAS-association domain family 1A (RASSF1A), p14, O(6)-methylguanine DNA methyltransferase (MGMT), and retinoid acid receptor beta2 (RARbeta) were determined in patients with monoclonal gammopathy of undetermined significance (MGUS; n = 29), smoldering multiple myeloma (SMM; n = 5), multiple myeloma (MM; n = 113), or plasma cell leukemia (PCL; n = 7) by methylation-specific polymerase chain reaction analysis.


RESULTS
Methylation frequencies for p16, TIMP3, p15, ECAD, DAPK, p73, RASSF1A, p14, MGMT, and RARbeta were as follows: 28%, 35%, 10%, 0%, 17%, 21%, 14%, 14%, 7%, and 0%, respectively, in patients with MGUS and 36%, 29%, 27%, 27%, 22%, 15%, 15%, 9%, 4%, and 0%, respectively, in patients with MM. Methylation of at least 1 of these genes was detected in 79% of patients with MGUS and in 80% of patients with MM. Although methylation of ECAD was not detected in patients with MGUS, it was observed frequently in patients with MM and with even greater frequency in patients with PCL. It is noteworthy that an association was found between ECAD methylation and poor prognostic markers in patients with MM.


CONCLUSIONS
Methylation of certain genes can be detected frequently in patients with monoclonal gammopathies. The current data suggest that methylation of ECAD is a marker of disease progression in patients with MM and PCL.
Seidl
Sonja
S
Clinical Division of Oncology, Department of Medicine I, University Hospital, Vienna, Austria.
Ackermann
Jutta
J
Kaufmann
Hannes
H
Keck
Andrea
A
Nösslinger
Thomas
T
Zielinski
Christoph C
CC
Drach
Johannes
J
Zöchbauer-Müller
Sabine
S
D000368:Aged; D014408:Biomarkers, Tumor; D015820:Cadherins / Q000235:genetics*; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010265:Paraproteinemias / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D016133:Polymerase Chain Reaction
D014408:Biomarkers, Tumor; D015820:Cadherins