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p16 Overexpression: A Potential Early Indicator of Transformation in Ovarian Carcinoma

C. Hu, MD

C. M. West

J. Clarke

G. P. Pharham, MD

T. H. Parmley, MD

S. Korourian, PhD

V. V. Baker, MD

Departments of Obstetrics and Gynecology, Biochemistry and Molecular Biology, and Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Division of Gynecologic Oncology, University of Michigan Medical Center, Ann Arbor, Michigan

T. J. O'Brien, PhD

Departments of Obstetrics and Gynecology, Biochemistry and Molecular Biology, and Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Division of Gynecologic Oncology, University of Michigan Medical Center, Ann Arbor, Michigan; Biomedical Biotechnology Center, 4301 W. Markham, Slot 718, Little Rock, AK 72205

Objective: The recently cloned gene p16 (MST 1) has been identified as a putative tumor suppressor gene that binds to CDK4 and CDK6 (cyclin-dependent kinases), preventing their interaction with cyclin D1 and thereby preventing cell cycle progression at the G1 stage. In addition, the p16 gene has been shown to have a high frequency of mutation in some tumor cell lines; however, it has also been shown that a much lower frequency of mutation occurs in primary tumors. This study investigated the mRNA expression level and mutation status of the p16 gene in ovarian tumors.

Methods: We performed quantitative polymerase chain reaction and direct cDNA sequencing analysis. To confirm the p16 protein level in ovarian tumors, Western blotting and immunohistochemical staining were performed. Expression levels of mRNA for the p16 gene relative to the ß-tubulin gene were examined in 32 ovarian tumors (24 carcinomas, six low malignant potential tumors, and two benign tumors) and six normal ovaries.

Results: The mRNA expression level of p16 was significantly elevated in 28 ovarian tumors (22 carcinomas, five low malignant potential tumors, and one benign tumor) compared with that of normal ovaries. Western blotting analysis and immunohistochemical staining confirmed elevated p16 protein levels in ovarian tumor samples. Among 32 ovarian tumors, cDNA sequencing of the p16 gene showed no p16 mutation resulting in a coding error, although one silent mutation and three polymorphisms were found.

Conclusions: Although p16 is seldom mutated in ovarian tumors, the overexpression of p16 in most ovarian tumor cases indicates a dysfunction in the regulatory complex for G1 arrest. Therefore, overexpression of p16 may be an important early event in the neoplastic transformation of the ovarian epithelium.

Key Words: p16 • mRNA expression • mutation status • ovarian cancer

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