LEPTIN, IGFS AND COLORECTAL ADENOMA CANCER RISK

描述（由申请人提供）： 流行病学研究一致表明，肥胖会增加结直肠癌及其常见前驱病变腺瘤性息肉的风险。这种关系的生物学机制可能涉及循环瘦素水平和胰岛素样生长因子（IGFs）的影响-两者似乎都增加了细胞增殖。IGF-1水平升高和IGFBP-3水平降低与结直肠腺瘤和癌症风险增加相关。作为我们已完成的以临床为基础的病例对照研究的扩展[结直肠癌的筛选标志物（P01 CA 74184）]，我们建议1）评估循环瘦素、IGF-1和IGFBP-3水平与结直肠腺瘤风险之间的关联，2）评估瘦素受体（LEPR）和IGFBP-3多态性与结直肠腺瘤之间的关联，以及3）在结肠镜阴性对照中检查LEPR和IGFBP-3多态性与循环瘦素和IGFs之间的基因型-表型关系。此外，我们计划探索上述相关性是否被常见的腺瘤危险因素所改变，特别是体重指数和外源性激素的使用。本研究招募了计划进行结肠镜检查的普吉特海湾团体健康合作社（GHC）的连续样本。在738名30-79岁的男性和女性中，160名被诊断为结直肠腺瘤，270名结肠镜检查阴性。在结肠镜检查之前，完成流行病学调查问卷并收集血液样本。使用免疫测定法测量循环瘦素、IGF-1和IGFBP-3水平，并对个体进行LEPR（GIn 223 Arg变化）和IGFBP-3（Gly 32Ala变化）多态性的基因分型。这一建议是一个有效的和成本效益的方法来调查瘦素，胰岛素样生长因子，他们的遗传变异和结直肠腺瘤的风险之间的关系。这项研究可能会深入了解肥胖与结直肠癌风险相关的生物学机制，并对癌症预防具有实际意义。

DESCRIPTION (provided by applicant): Obesity has been consistently shown in epidemiologic studies to increase risk of colorectal cancer and its common precursor lesion, adenomatous polyps. The biological mechanism underlying this relationship may involve effects of circulating leptin levels and insulin-like growth factors (IGFs) - both appear to increase cell proliferation. Elevated IGF-1 levels and low IGFBP-3 levels have been associated with increased risk of colorectal adenoma and cancer. As an extension to our completed clinic-based, case-control study [Screening Markers for Colorectal Cancer (P01 CA74184)], we propose to 1) evaluate the association between circulating leptin, IGF-1 and IGFBP-3 levels and colorectal adenoma risk, 2) assess the association between leptin receptor (LEPR) and IGFBP-3 polymorphisms and colorectal adenomas, and 3) examine the genotype-phenotype relationships between LEPR and IGFBP-3 polymorphisms and circulating leptin and IGFs in colonoscopy-negative controls. Additionally, we plan to explore whether the above associations are modified by common adenoma risk factors, especially body mass index and exogenous hormone use. A sequential sample of enrollees of Group Health Cooperative (GHC) of Puget Sound scheduled for colonoscopies was recruited into this study. Of the 738 men and women aged 30-79 years, 160 were diagnosed with colorectal adenoma and 270 were colonoscopy negative. Prior to colonoscopy, an epidemiologic questionnaire was completed and blood samples were collected. Circulating leptin, IGF-1, and IGFBP-3 levels were measured using immunoassays, and individuals will be genotyped for polymorphisms in LEPR (a GIn223Arg change) and IGFBP-3 (a Gly32Ala change). This proposal is an efficient and cost-effective approach to the investigation of the relationship between leptin, IGFs, their genetic variation, and colorectal adenoma risk. This study may provide insights into the biologic mechanisms whereby obesity is associated with colorectal cancer risk, as well as have practical implications for cancer prevention.