Methylation of tumor suppressor gene p16 and prognosis of epithelial ovarian cancer
Introduction
Tumor suppressor gene p16 (INK4A/MTS1/CDKN2) encodes a 15.8-kDa protein that interacts with cyclin-dependent kinase CDK4 and CDK6. CDK4 and CDK6 bind to cylcin D regulating cell cycle progression from G1 to S phases. Binding of p16 to CDKs inhibits the formation of CDK/cyclin D complex, resulting in cell cycle arrest at G1 phase. The role of p16 in cell cycle control is believed to be involved in cancer development and progression [1], [2], [3], [4], [5]. Loss of p16 expression has been observed in many types of cancer [2]. Genetic and epigenetic alterations, including homozygous deletion, point mutation, and promoter methylation, are considered to be responsible for the loss of p16 activity [5], [6].
Promoter methylation has been recognized as an important mechanism in regulation of gene expression [7], [8]. Aberrant methylation of p16 promoter has been found in many forms of cancer, including ovarian cancer [5]. Clinical studies indicate that p16 expression is undetectable in about a third of ovarian cancer cases [9], [10], [11], [12] and that patients with low p16 expression have poor responses to chemotherapy and unfavorable survival outcome [11], [13]. Cell culture experiments demonstrate that reintroducing functional p16 into p16-null ovarian cancer cells results in inhibition of cell growth and increases in apoptosis, suggesting that p16 plays a role in ovarian cancer progression [14].
Epithelial ovarian cancer is one of the most lethal malignancies; 5-year survival of patients with the disease is only 50% [15], [16]. To improve our understanding of ovarian cancer progression and to search for molecular markers for prediction of ovarian cancer prognosis, we analyzed p16 promoter methylation in epithelial ovarian cancer tissue and examined its association with patient progression-free and overall survival.
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Study subjects
Between October 1991 and February 2000, 270 patients underwent surgery for ovarian cancer in the Department of Gynecology, Gynecologic Oncology Unit, at University of Turin in Italy. Of the 270 patients, 18 had borderline tumors (histological grade 0) and 2 patients had metastatic cancer to the ovary. One patient did not have sufficient tissue specimen for analysis. The final number of patients included in this study was 249, all of who had primary epithelial ovarian cancer. The age of these
Results
Of the 249 tumor samples analyzed, 100 were found to be positive for p16 promoter methylation, which accounted for 40% of the samples. Patient age at diagnosis was not significantly different between patients with and without p16 methylation. The mean age was 57.8 years for patients with methylation and 56.9 years for those without methylation (P = 0.576). Table 1 shows the distributions of p16 methylation in relation to clinical and pathological variables. Compared to patients without p16
Discussion
In this study, we found p16 promoter methylation in 40% of epithelial ovarian cancer. Compared to those without p16 methylation, patients with p16 methylation had a 50% increase in risk for disease progression. Moreover, the increased risk for disease progression was independent from clinical and pathological factors, suggesting that p16 methylation may have values in predicting ovarian cancer prognosis. The study findings seem to support the notion that p16 methylation in ovarian cancer is
Acknowledgements
Drs. D. Katsaros, S. Fracchioli, and I.A. Rigault de la Longrais are partially supported by AIRC (Italian Association for Cancer Research).
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