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

项目 1：氧甾醇和结直肠腺瘤：循环浓度和基因型

• 批准号: 10091539
• 负责人: Michael N Passarelli
• 金额: $ 14.52万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091539
• 关键词: 25-hydroxycholesterol; 27-hydroxycholesterol; Aberrant crypt foci; Adenomatous Polyps; Adipose tissue; Adult; Age-Years; Analytical Chemistry; Anatomy; Apoptosis; Atherosclerosis; Bile Acid Biosynthesis Pathway; Biological; Blood; Blood Circulation; Breast Cancer Model; Breast Cancer Risk Factor; Calcium; Caliber; Cancer Etiology; Candidate Disease Gene; Case-Control Studies; Cessation of life; Cholesterol; Cholesterol Homeostasis; Chronic Disease; Clinical Trials; Colonoscopy; Colorectal; Colorectal Adenocarcinoma; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Consensus; Data; Development; Dyslipidemias; Early Diagnosis; Estrogen Receptor beta; Estrogens; Exhibits; Fasting; Genes; Genome Scan; Genotype; Heart; Heterogeneity; High Density Lipoproteins; High Pressure Liquid Chromatography; High grade dysplasia; Hormonal; Human; Hydroxycholesterols; Hydroxylation; Hypertriglyceridemia; Incidence; Individual; Inflammatory; Investigation; Lead; Lesion; Life Style; Ligands; Link; Lipids; Liver; Liver X Receptor; Location; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Metabolic syndrome; Metabolism; Molecular Epidemiology; Mucous Membrane; Nuclear; Participant; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Placebos; Plasma; Polypectomy; Polyps; Prevention; Prevention strategy; Property; Randomized; Recurrence; Research Project Grants; Risk; Risk Factors; Role; Selective Estrogen Receptor Modulators; Serrated Adenoma; Source; Specimen; Suggestion; Testing; Tissues; United States; Variant; Villous; Vitamin D; Woman; adenoma; calcium supplementation; cancer risk; carcinogenesis; cell growth; colon carcinogenesis; colorectal cancer risk; cytokine; disorder risk; epidemiology study; follow-up; genetic analysis; genetic association; genetic risk factor; genetic variant; genome wide association study; genome-wide; high risk; liquid chromatography mass spectrometry; macrophage; malignant breast neoplasm; men; mortality; mouse model; neoplastic; novel; preclinical study; premalignant; prevent; randomized placebo-controlled clinical trial; recruit; study population

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.

项目1摘要 结直肠癌是美国癌症相关死亡的第二大原因， 通过早期发现癌前腺瘤性息肉（腺瘤）来预防。个人与大 晚期病理的腺瘤、无蒂锯齿状腺瘤或任何大小的多发性腺瘤， 特别是增加了发展后续结肠直肠癌的风险。血脂异常和代谢 综合征是结直肠肿瘤潜在危险因素，但有不一致的证据表明， 胆固醇浓度或使用降脂药物与结肠直肠腺瘤或癌症有关。 本课题主要研究胆固醇生物合成中的第一步代谢产物 胆汁酸，被称为氧化固醇，现在可以在人体循环中检测到浓度， 分析化学的最新突破最丰富的循环氧固醇之一，27- 羟基胆固醇（27-HC）已显示在 临床前研究。最近发现27-HC作为选择性雌激素受体调节剂发挥作用， 与乳腺癌的发展有关结肠直肠癌也容易受到激素的影响; 尽管使用外源性雌激素会增加患乳腺癌的风险，但雌激素往往会降低患乳腺癌的风险。 结肠直肠癌的症状。除了27-HC之外，已知几种其他氧化固醇种类促进细胞凋亡， 募集炎性细胞因子，包括25-羟基胆固醇（25-HC）、7β-羟基胆固醇（7-HC）和 4β-羟基胆固醇（4-HC）。我们将测试这些药物的血药浓度之间的关系， 维生素D和钙息肉预防研究中氧化固醇与结直肠腺瘤复发的关系 一项已完成的、多中心、随机、安慰剂对照、部分析因的维生素D和/或 补充钙剂预防腺瘤复发。共有1，622名男性和女性， 在首次息肉切除术后接受随访结肠镜检查长达5年的结直肠腺瘤， 可用的空腹血浆和先前收集的生殖系基因型数据。氧固醇将从以下测量： 使用高效液相色谱-质谱法对储存的标本进行分析。其次，我们将测试 与25-、7-和4-HC的相关性，并探索腺瘤相关性的异质性来源。 腺瘤的病理和解剖位置。我们还计划在2010年进行两项遗传关联研究。 与腺瘤复发的关系，重点关注以下变体：1）已知在27-HC中起作用的候选基因 2）全基因组扫描，以发现和复制与循环27-HC的新关联 浓度的探索性分析将通过27-HC血液水平评估腺瘤复发是否是 根据这些基因型的异质性。这是第一次评估血液氧化固醇与结肠直肠癌的关系， 腺瘤将有助于我们了解胆固醇代谢如何与致癌作用相关， 最终形成更有效的预防战略。