结直肠癌筛查与早期诊断血清自身抗体标志物筛选、验证及预测模型的研究

Screening can effectively reduce the burden of colorectal cancer (CRC). Established non-invasive screening modalities are limited by poor sensitivity for detecting CRC precursors and relatively low compliance rates. Current researches have revealed that tumor-associated autoantibodies are produced by humoral immune system which specifically identifies and targets tumor-associated antigens, therefore serve as promising biomarker candidates in cancer early detection. However, majority of published studies adopted hospital-based retrospective design using relatively small sample sizes, and lacked independent and prospective evaluation regarding the diagnostic performance of biomarkers. Our group have previously identified several promising autoantibody biomarkers which showed good diagnostic performance in detecting CRC and its precursors. Therefore, based on previous findings, this study will use high-throughput methods to screen for and identify novel CRC and precursor specific autoantibody biomarkers through a multi-step approach. Afterwards, using prospectively collected blood samples from an established population-based CRC screening cohort, multiple case-control studies (CRC vs. precursors vs. healthy controls) will be carried out. Optimal diagnostic prediction models combining CRC risk factors and serum levels of autoantibodies will be constructed, and its diagnostic performance will be independently evaluated and validated. The findings of this project will provide important scientific evidence in precise identification of high risk population and development of novel effective non-invasive tests for CRC screening in the future.

筛查是降低结直肠癌负担的有效手段。但现有的非侵入性筛查手段存在着癌前病变诊断灵敏度低和人群依从性差等局限性。近年来的研究发现，肿瘤相关自身抗体是由免疫系统特异性识别肿瘤相关抗原而产生，是极具应用前景的早期诊断标志物。目前已发表的大多为以医院为基础的小样本、回顾性研究，且缺乏对生物标志物诊断效能的独立性和前瞻性验证。课题组前期已识别若干对早期结直肠癌和癌前病变有较好诊断能力的自身抗体标志物。因此，拟在此基础上，采用高通量检测手段多阶段筛选与结直肠癌和癌前病变特异相关的自身抗体标志物。随后基于已建立的大型前瞻性结直肠癌筛查队列，采用病例对照研究设计（结直肠癌 vs 癌前病变 vs 健康对照），结合结直肠癌高危因素和自身抗体水平，构建最优化的诊断预测模型，并对诊断效能进行独立性的验证和评价。本课题的顺利实施将为精准识别结直肠癌高危人群以及开发新型有效的结直肠癌非侵入性筛查手段提供重要理论依据。

筛查和早诊早治是降低结直肠癌死亡率的有效手段。现有的非侵入性筛查手段存在着癌前病变诊断灵敏度低和人群依从性差等局限性。肿瘤相关自身抗体是由免疫系统特异性识别肿瘤相关抗原而产生，是极具应用前景的早期诊断标志物。本项目基于前期研究基础上，确定了26种候选自身抗体标志物，探讨其在结直肠癌筛查和早期诊断中的应用价值。基于在前期研究中建立的人群结直肠癌筛查队列资源，项目组采用多阶段研究设计对候选自身抗体标志物进行了高通量筛选、验证和评价。本研究发现ALDH1B1、UQCRC1、CTAG1和CENPF等4种新型血清自身抗体标志物对结直肠癌和进展期腺瘤具有较好的早期诊断潜能。研究发现ALDH1B1抗体的诊断效能最高，对结直肠癌的ROC曲线下面积（AUC）为0.70，灵敏度为75.68%，特异度为63.06%；对进展期腺瘤的AUC为0.74，灵敏度为62.31%，特异度为73.87%。4种血清自身抗体标志物联合对结直肠癌和进展期腺瘤的诊断效能进一步提升，AUC可以达到0.79。此外，项目组也利用人群结直肠癌筛查队列研究和随机对照研究资源，对结肠镜、免疫法粪便隐血试验（FIT）、新型个体化筛查方案在人群筛查中的依从性、病变检出率、内镜资源负荷等指标进行了系统分析，且鉴别出一系列与中国人群结直肠肿瘤相关的环境危险因素。本项目的研究发现具有较强的转化应用价值，将对开发结直肠癌筛查和早期诊断标志物、构建结直肠癌风险评估模型、形成适合于中国人群的个体化精准化结直肠癌筛查和干预策略提供重要研究证据。