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Loss
of p16 Protein Expression Associated with Methylation of the p16INK4A
Gene Is a Frequent Finding in Hodgkin's Disease |
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Juan F. García,
Raquel Villuendas, Patrocinio Algara, Ana I. Sáaez, Lidia Sáanchez-Verde,
Juan C. Martínez-Montero, Pedro Martínez, and Miguel A. Piris |
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Department
of Pathology (JFG, AIS, JCM-M, MAP), and Department of Genetics (RV, PA,
LS-V, PM), "Virgen de la Salud" Hospital, Toledo, Spain |
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SUMMARY: p16 protein binds
and inactivates cyclin D-CDK4/6 complexes, stopping the cell cycle at the
G1/S boundary. Loss of p16 expression is found frequently in human cancer
tissues, often resulting from allelic loss or promoter region hypermethylation
in non-Hodgkin's lymphomas. Hodgkin's disease has been shown to be a monoclonal
neoplasm of B-cells in which a majority of cells are cycling. In the attempt
to identify hypothetical CDK inhibitor inactivation that could explain the
accumulation of proliferating cells, we decided to focus on the p16INK4A
gene. To determine whether inactivation of this gene is implicated in the
development of Hodgkin's disease, we immunostained 40 cases with a monoclonal
antibody for the p16 protein. At the same time, we used a methylation-specific
PCR technique to determine the methylation status of exon 1 of the p16INK4A
gene in 23 cases in this series. Loss of p16 expression was found in 30
of 37 cases (absence of expression in most Hodgkin's/Reed-Sternberg cells,
with a normal scattered pattern of p16 expression in the reactive background).
Only seven samples showed nuclear p16 expression in a significant proportion
of large tumoral cells. In agreement with this finding, hypermethylation
of p16INK4A gene was found in 14 of 23 cases by PCR. All the
p16 cases found positive by immunohistochemistry also showed unmethylated
DNA. These results show that loss of p16 protein expression is usually observed
in Hodgkin's/Reed-Sternberg cells in Hodgkin's disease, frequently associated
with p16INK4A gene hypermethylation. The high frequency of abnormal
methylation found in this study suggests that this genetic event may play
an important role in the pathogenesis of the disease. |
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