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Methylation and Messenger RNA Expression of p15^INK4b but Not p16^INK4a Are Independent Risk Factors for Ovarian Cancer

Authors' Affiliations: Departments of ¹ Epidemiology, ² Gynecologic Oncology, and ³ Molecular Therapeutics, The University of Texas M.D. Anderson Cancer Center and ⁴ The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas

Requests for reprints: Qingyi Wei, Department of Epidemiology, Unit 189, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3020; Fax: 713-563-0999; E-mail: qwei{at}mdanderson.org.

Purpose: The purpose of this research was to compare methylation status and mRNA expression of p15^INK4b and p16^INK4a in serous epithelial ovarian cancer tissues and normal ovarian tissues.

Experimental Design: We analyzed the DNA methylation status and mRNA expression of p15^INK4b and p16^INK4a in 52 ovarian cancer specimens and 40 normal ovarian specimens by using methylation-specific PCR and real-time reverse transcription-PCR, respectively.

Results: Although the p15^INK4b and p16^INK4a mRNA expression levels were highly correlated with each other (P < 0.001), the methylation status did not seem to be linked with levels of mRNA expression, as no association between the two events was found for either gene. Promoter hypermethylation of p15^INK4b was more common in ovarian cancer (30.8% for the 52 cases) than in normal ovaries (5% for the 40 controls without ovarian cancer; P = 0.005) but not methylation of p16^INK4a (25% for cancer versus 37.5% for normal; P = 0.288). The relative mRNA expression levels of p15^INK4b were significantly lower in ovarian cancer (12.9%) than in normal ovaries (41.7%; P = 0.008) but not those of p16^INK4a (27% for cases versus 32.8% for controls; P = 0.754). Only high methylation rate and low mRNA expression of p15^INK4b were independent risk factors for ovarian cancer (adjusted odds ratio, 5.67; 95% confidence interval, 0.85-37.9 for high methylation rate and odds ratio, 8.98; 95% confidence interval, 1.58-50.9 for low mRNA expression, respectively).

Conclusions: Our results suggest that epigenetic alterations in p15^INK4b but not p16^INK4a have an important role in ovarian carcinogenesis and that mechanisms other than methylation may exist to reduce gene expression of p15^INK4b in ovarian cancer.

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