Project 1: Oxysterols and colorectal adenomas: circulating concentrations and genotypes

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PROJECT 1 ABSTRACT Colorectal cancer is the second leading cause of cancer-related death in the United States, by can be prevented by the early detection of premalignant adenomatous polyps (adenomas). Individuals with large adenomas with advanced pathology, sessile serrated adenomas, or multiple adenomas of any size are at particularly increased risk of developing a subsequence colorectal cancer. Dyslipidemia and metabolic syndrome are potential risk factors for colorectal neoplasia, but there is inconsistent evidence that blood cholesterol concentrations or use of lipid-lowering drugs are associated with colorectal adenomas or cancer. For this research project, we will focus on the first-step metabolism products of cholesterol in the biosynthesis of bile acids, known as oxysterols, which are now detectable in human circulation at concentrations using recent breakthrough in analytical chemistry. One of the most abundant circulating oxysterols, 27- hydroxycholesterol (27-HC), has been shown in exhibit pro-inflammatory and pro-migratory properties in preclinical studies. 27-HC has recently been found to function as a selective estrogen receptor modulator and has been implicated in breast cancer development. Colorectal cancer also is susceptible to hormonal effects; whereas use of exogenous estrogens increases the risk of breast cancer, estrogens tend to decrease the risk of colorectal cancer. In addition to 27-HC, several other oxysterol species are known to promote apoptosis and recruit inflammatory cytokines, including 25-hydroxycholesterol (25-HC), 7β-hydroxycholesterol (7-HC), and 4β-hydroxycholesterol (4-HC). We will test the association between plasma concentrations of theses oxysterols and colorectal adenoma recurrence in the Vitamin D and Calcium Polyp Prevention Study, a completed, multicenter, randomized, placebo-controlled, partial-factorial clinical trial of vitamin D and/or calcium supplementation for the prevention of recurrent adenomas. In total, 1,622 men and women with colorectal adenomas who received a follow-up colonoscopy up to 5 years after their initial polypectomy have available fasting plasma and previously-collected germline genotype data. Oxysterols will be measured from stored specimens using high-performance liquid chromatography-mass spectrometry. Secondarily, we will test associations with 25-, 7-, and 4-HC, and explore sources of heterogeneity in the associations by adenoma pathology and anatomic location of adenomas. We also plan to conduct two genetic association studies in relation to adenoma recurrence, focusing on variants from: 1) candidate genes known to function in 27-HC metabolism; and 2) a genome-wide scan to discover and replicate novel associations with circulating 27-HC concentrations. Exploratory analyses will evaluate whether adenoma recurrence by 27-HC blood levels is heterogeneous according to these genotypes. This first assessment of blood oxysterols in relation to colorectal adenomas will contribute to our understanding of how cholesterol metabolism related to carcinogenesis, and ultimately lead to more effective preventive strategies.