Endometrial cancer is the most common gynecologic malignancy in the United States. Women with heriditary nonpolyposis colrectal cancer (NHPCC) gene mutations are at an increased risk for developing endometrial cancer, and represent an ideal target population for examination of possible biomarkers for this cancer. This study is to identify potential surrogate endpoint biomarkers that are modulated by DepoMedroxyprogesterone Acetate (DepoMPA) versus a combination oral contraceptive pill (OCP, ethinyl estradiol/norgestrel) in women at high-risk for endometiral cancer. Women with HNPCC will be randomized to DepoMPA or OCP for three months. Each women will receive a pre- and post-treatment transvaginal ultrasound and endometrial biopsy. The biopsies will be analyzed for: 1. Morphological Markers - histology, proliferative index, apoptosis 2. Quantitive PCR transcript analysis: A. Determinants of Response (estrogen receptor, progesterone receptor, SRC-1, CBP) B. Paraquine/Autocrine Pathway #1 - Wnt 5a, Wnt 2, Friz 5, Friz 7, sFRP1, sFRP4, APC, beta-catenin C. Paraquine/Autocrine Pathway #2 - IGF-1, IGF-2, IGFBP-3, IGFBP-5, IGFBPR-1 D. Cytokine Regulators of Proliferation - TGF-alpha, EGFR, TNF-alpha, TGF-beta 1, TGF-beta receptor E. Retinoids and Related Growth Regulators - RALDH2, RAR-beta, RaOH, PPAR delta 3. Oncogenes and Tumor Suppressor Genes - K-ras and PTEN 4. Microstatellite Instability 5. Loss of heterozygosity of mismatch repair genes A study size of 64 women, 32 women per arm, will give a 80% power to detect an increase or decrease in the value of a given biomarker, with an alpha of 0.05%.
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