血清chemerin水平与结直肠癌及其癌前病变发生风险的分子流行病学研究

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies worldwide. CRC derives mostly from colorectal adenomas, which are well recognized as CRC precursor lesions. Removal of adenomas reduces more than 50% of the incidence and mortality from CRC in western countries. Research on the etiology of CRC and adenoma maybe essential for the identification of biomarkers with high sensitivity and specificity which could be used in the early detection and risk prediction of CRC. Recently, chemerin was proposed as an adipokine to link obesity, insulin resistance, and chronic inflammation of adipose tissue, suggesting a potentially significant role in colorectal carcinogenesis. Our previous analyses revealed that the expression of chemerin coding gene RARRES2 was significantly lower in colorectal cancer tissue compared with tumor adjacent normal tissue or tissue from healthy controls. In the current study, we plan to conduct a case-control study and a Mendelian randomization study to explore the association between serum chemerin levels and risk of developing colorectal cancer and adenoma. The results of this study will elucidate the potential of serum chemerin levels as biomarker for CRC early detection and risk prediction, as well as provide further evidence for the role of chemerin in the development of CRC and adenoma.

结直肠癌是常见的消化系统恶性肿瘤，其发生发展是多阶段、多步骤、内外因交互作用的结果，且具有较长的癌前病变过程和明显的分子特征。深入探索结直肠癌及其癌前病变的病因学和发生机制，寻找理想的筛查和早期诊断标志物，及时发现并清除腺瘤和早期癌是降低结直肠癌发病率、病死率的有效措施。近期研究发现，脂肪因子chemerin与肥胖、脂质代谢、胰岛素抵抗、炎症反应等密切相关，可能在结直肠癌的发生发展中起了至关重要的作用。本研究拟结合课题组前期工作基础，采用病例对照研究设计，探讨血清chemerin水平与结直肠癌、腺瘤发生的关联，进一步采用孟德尔随机化方法，分析影响血清chemerin水平的遗传变异与腺瘤、结直肠癌发生的关联，并综合探讨遗传变异、生活方式等环境因素的交互作用对腺瘤、结直肠癌发生的影响，以期为进一步阐明结直肠癌的病因学和发生机制、实现癌前病变和早期癌的风险预测以及预防关口前移提供重要线索。

结直肠癌是最常见的消化系统恶性肿瘤之一，其发生发展是遗传因素和环境因素共同作用的结果，其中，脂肪因子可能起了至关重要的作用。本研究采用了以自然人群为基础的大样本病例对照研究，探讨了趋化因子（chemerin）等多个脂肪因子编码基因相关遗传变异与结直肠腺、结直肠癌发生风险的关联，发现血清Chemerin水平相关遗传变异位点rs347344与结直肠癌发生之间存在统计学临界相关(aOR=1.31，95% CI：0.98-1.74)；脂联素相关遗传变异rs1501299与腺瘤发生风险呈正相关（aOR=1.21，95% CI：1.00-1.46）。按吸烟、饮酒和饮茶进行分层分析后发现，rs1501299、rs347344与上述生活方式之间存在的交互作用可能会影响结直肠腺瘤、结直肠癌的易感性。这些结果提示，脂肪因子Chemerin、脂联素可能与结直肠癌的发生有关，基因-环境交互作用可能影响结直肠腺瘤和结直肠癌的发病风险。在项目资助下，发表学术论文15篇，其中SCI收录11篇（单篇最高影响因子9.496），参加国内外学术交流，多次获优秀论文奖。本项目的开展，为结直肠癌的病因学研究提供了先进、可行的技术和方法，研究结果为结直肠癌的发生发展机制及预防控制措施研究提供了科学依据。