Role of Circadian Factors in Inflammation and Colorectal Adenoma Risk

结直肠癌 (CRC) 是最常见和最致命的癌症之一。在南卡罗来纳州，我们的团队 已记录了超过全国比率的种族 CRC 差异。大多数结肠肿瘤源自腺瘤 （腺瘤性息肉）通过结肠镜检查筛查发现。胃肠道 (GI) 炎症和 异常 DNA 甲基化是导致腺瘤形成和 CRC 风险的关键过程。睡眠不足和 昼夜节律紊乱会诱发炎症、改变 DNA 甲基化并增加 CRC 风险。非洲- 美国人 (AA) 与欧洲美国人 (EA) 的内源昼夜节律不同，他们 与 EA 相比，他们更有可能睡眠质量不佳和压力过大（动态负荷过重或“风化”）。这个案例—— 对照研究将检验昼夜节律过程和睡眠的破坏与以下因素相关的假设： 接受结肠镜筛查的 AA 和 EA 患者的炎症和腺瘤风险。分子 计时是由“时钟基因”控制的，“时钟基因”通过表观遗传机制调节昼夜节律基因的表达。 时钟基因可以调节炎症（例如 TNFα、IL-6 表达），并且它们可以充当肿瘤抑制因子 （例如，“Period”或 PER 基因）。我们的研究表明 PER 中的遗传变异或异常甲基化 基因与腺瘤风险增加有关，睡眠障碍会增加结直肠癌风险。褪黑激素是 一种时钟调节激素，通过与其结合来抑制胃肠道炎症并抑制结肠肿瘤生长 细胞受体（MT-1、RORα）。这项研究将描述生物行为昼夜节律破坏指标 （睡眠障碍、社交时差、疲劳、压力），以及关键分子相关因素（PER3 基因型和 甲基化：时钟基因 [PER1、PER2、PER3]；时钟控制基因[MT-1、RORα、TNFα、IL-6]；和 整体 DNA 甲基化 [LINE-1]）以确定其在炎症和腺瘤风险中的作用。生物行为 该框架将实现以下具体目标： 1) 在患者中进行病例对照研究 接受结肠镜筛查以确定是否存在昼夜节律紊乱指标（DNA 甲基化、 生物行为、遗传）与相对于对照的腺瘤病例状态相关，并且如果这种关系是 按种族修改（N=1,000；400 例病例，600 例对照）； 2) 确定昼夜节律紊乱指标是否 与正常胃肠道组织的炎症相关（TNFα、IL-6 mRNA 表达）； 3）判断是否 行为和分子昼夜节律紊乱指标是相关的； 4) 在腺瘤病例中，确定是否 腺瘤中候选昼夜节律基因的甲基化与正常胃肠道组织不同。我们的团队拥有强大的 提供高质量结肠镜检查服务以及让 AA 和 EA 社区参与其中的记录 研究。前瞻性数据收集（相对于结肠镜检查）和有效、定量生物行为的使用 分子措施将限制潜在的偏见引入。这项研究将严格审查 基于昼夜节律的行为和分子风险因素，因为它们与胃肠道炎症和结直肠相关 腺瘤风险。基于昼夜节律的风险因素可以作为预防结直肠癌的新颖、可修改的目标。

Colorectal cancer (CRC) is among the most common and deadly forms of cancer. In South Carolina, our group has documented racial CRC disparities that exceed national rates. Most colon tumors arise from adenomas (adenomatous polyps) that are detected via a screening colonoscopy. Gastrointestinal (GI) inflammation and aberrant DNA methylation are key processes driving adenoma formation and CRC risk. Sleep loss and circadian rhythm disruption can induce inflammation, alter DNA methylation, and increase CRC risk. African- Americans (AAs) differ from European-Americans (EAs) in their endogenous circadian timing, and they are more likely than EAs to have poor sleep and excessive stress (allostatic overload or ‘weathering’). This case- control study will test the hypothesis that disruption of circadian processes and sleep is associated with inflammation and adenoma risk among AA and EA patients receiving a screening colonoscopy. Molecular timekeeping is controlled by ‘clock genes’ that regulate circadian gene expression via epigenetic mechanisms. Clock genes can modulate inflammation (e.g., TNFα, IL-6 expression), and they act as tumor suppressors (e.g., the ‘Period’ or PER genes). Our research suggests that genetic variation or aberrant methylation in PER genes is associated with increased adenoma risk, and that sleep disorders can increase CRC risk. Melatonin is a clock-regulated hormone that suppresses GI inflammation and inhibits colon tumor growth by binding to its cellular receptors (MT-1, RORα). This study will characterize biobehavioral circadian disruption indicators (sleep disturbances, social jet lag, fatigue, stress), along with key molecular correlates (PER3 genotype and methylation of: clock genes [PER1, PER2, PER3]; clock-controlled genes [MT-1, RORα, TNFα, IL-6]; and global DNA methylation [LINE-1]) to determine their role in inflammation and adenoma risk. A biobehavioral framework will address the following Specific Aims: 1) Conduct a case-control study among patients undergoing a screening colonoscopy to determine whether circadian disruption indicators (DNA methylation, biobehavioral, genetic) are associated with adenoma case status relative to controls, and if the relationship is modified by race (N=1,000; 400 cases, 600 controls); 2) Determine if circadian disruption indicators are associated with inflammation in normal GI tissue (TNFα, IL-6 mRNA expression); 3) Determine whether behavioral and molecular circadian disruption indicators are related; 4) Among adenoma cases, determine if methylation of candidate circadian genes in adenomas differs from normal GI tissue. Our team has a strong track record of providing high quality colonoscopy services and in engaging AA and EA communities in research. Prospective data collection (relative to colonoscopy) and the use of valid, quantitative biobehavioral and molecular measures will limit the potential introduction of bias. This study will rigorously examine circadian-based behavioral and molecular risk factors as they relate to GI inflammation and colorectal adenoma risk. Circadian-based risk factors may serve as novel, modifiable targets for CRC prevention.