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

项目1摘要 结直肠癌是美国癌症相关死亡的第二大原因， 通过及早发现癌前腺瘤性息肉(腺瘤)来预防。个人拥有大量的 病理进展期的腺瘤、无柄锯齿状腺瘤或任何大小的多发性腺瘤 尤其是增加了继发结直肠癌的风险。血脂异常与代谢 证候是结直肠肿瘤的潜在危险因素，但有不一致的证据表明血液 胆固醇浓度或降脂药物的使用与结直肠腺瘤或癌症有关。 在本研究项目中，我们将重点研究胆固醇在生物合成中的第一步代谢产物。 胆汁酸，称为氧化甾醇，现在可以在人体循环中检测到浓度为 分析化学的最新突破。一种最丰富的循环中的氧甾醇，27- 羟基胆固醇(27-HC)，已显示出促炎和亲迁移特性在 临床前研究。最近发现27-HC是一种选择性雌激素受体调节剂， 与乳腺癌的发生有关。结直肠癌也容易受到激素的影响； 虽然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风险。 结直肠癌。除27-HC外，已知的其他几种氧固醇物种可促进细胞凋亡和 招募炎性细胞因子，包括25-羟基胆固醇(25-HC)，7-β-羟基胆固醇(7-HC)，以及 4β-羟基胆固醇(4-HC)。我们将测试这些药物的血浆浓度之间的关联 维生素D和钙息肉预防研究中氧类固醇与结直肠腺瘤复发的关系 维生素D和(或)维生素D的完整、多中心、随机、安慰剂对照、部分因素临床试验 补钙预防腺瘤复发。总共有1622名男性和女性患有 在初次息肉切除后接受结肠镜检查长达5年的结肠腺瘤患者有 可用的空腹血浆和之前收集的生殖系基因数据。氧合甾醇将从 保存标本采用高效液-质联用技术。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 腺瘤的病理和解剖定位。我们还计划在年内进行两项基因关联研究 与腺瘤复发的关系，侧重于以下变异：1)已知在27-HC中起作用的候选基因 新陈代谢；以及2)全基因组扫描以发现和复制与循环27-HC的新关联 浓度。探索性分析将通过27-HC血液水平来评估腺瘤复发 根据这些基因类型的异质性。首次评估血液中的氧固醇值与结直肠的关系 腺瘤将有助于我们理解胆固醇代谢如何与癌症发生有关，以及 最终导致更有效的预防战略。

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.