p16/INK4a gene inactivation by hypermethylation is associated with aggressive variants of monoclonal gammopathies.
BACKGROUND
A model of a stepwise malignant transformation has been proposed for the pathogenesis of monoclonal gammopathies. In this model, cell cycle regulators play a central role as a source of genetic events; particularly, p16/INK4a gene acts as a tumoral suppressor gene and, recently, inactivation of this gene through a methylation mechanism, has been observed in multiple myeloma patients. Under the diagnosis of monoclonal gammopathies there is a broad spectrum of disorders with very different outcomes, ranging from indolent courses, such as those of monoclonal gammopathy of undetermined significance, Waldeströn macroglobulinemia and smoldering multiple myeloma, to aggressive diseases such as symptomatic MM and primary plasma cell leukemia. To the best of our knowledge, the activity of p16 gene has not been evaluated and compared in these different subtypes of monoclonal gammopathies.


METHODS
The methylation status of the p16 gene was analysed in a group of 159 patients with monoclonal gammopathies (40 monoclonal gammopathy of uncertain significance, eight Waldenström Macroglobulinemia, eight smoldering multiple myeloma, 98 symptomatic multiple myeloma and five primary plasma cell leukemia) using three different assays (restriction enzymes and PCR or S-B and modification by sodium bisulphite).


RESULTS
Forty-one of 98 MM patients (41.8%) as well as four of the five (80%) primary PCL patients showed methylation of the p16 gene, while none of the patients with monoclonal gammopathy of undetermined significance, Waldenström Macroglobulinemia or smoldering multiple myeloma displayed a methylation status.


CONCLUSIONS
These findings suggest that the methylation of the p16 gene could be a relevant oncogenic event in the monoclonal gammopathies evolution being associated with the most aggressive forms.
Mateos
M V
MV
Hematology Service, University Hospital of Salamanca, Spain.
Garcia-Sanz
R
R
López-Pérez
R
R
Balanzategui
A
A
González
M I
MI
Fernández-Calvo
J
J
Moro
M J
MJ
Hernández
J
J
Caballero
M D
MD
González
M
M
San Miguel
J F
JF
D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000502:physiology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects; D018450:Disease Progression; D020868:Gene Silencing; D019942:Genes, p16; D007952:Leukemia, Plasma Cell / Q000235:genetics / Q000473:pathology; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D010265:Paraproteinemias / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D013447:Sulfites / Q000494:pharmacology; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics / Q000473:pathology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D013447:Sulfites; D004247:DNA; C009279:sodium bisulfite