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.
