循环肿瘤DNA突变和甲基化检测在胃癌筛查和预后评估中的作用

Gastric cancer (GC) remains the second most common cancer and leading cause of cancer-related death in China. Although recent achievements in cancer diagnosis and therapeutic strategies have improved the clinical outcomes, 5-year survival rate is still less than 30%. Many patients are diagnosed with GC in its advanced stage due to lack of early diagnostic techniques. Failure to identify patients with high-risk of metastasis and recurrence has also resulted in an unsatisfactory prognosis of GC patients. Circulating tumor DNA (ctDNA) carries cancer-specific genetic mutations and epigenetic aberrations, which may enable us to perform a noninvasive 'liquid biopsy' for screening and monitoring of cancer. .This proposed project will investigate the optimal gene panel for early diagnosis and prognosis evaluation of GC based on the ongoing prospective GC cohort study. The driver gene mutations and target gene methylations of ctDNA were monitored in different groups, including: GC patients and controls; matched cases of pre-surgery and post-surgery; before and after remission. Integrated analysis of ctDNA mutations and methylations will be carried out, and DNAPanels with the best diagnostic performances and prognosis performances will be identified. The risk prediction models will be established to integrate the optimal panel with epidemiological risk factors and clinical data, precisely evaluating individual risk of GC and recurrence. Thus, this study aims at identification of cases with higher risks of gastric cancer and GC recurrence, enabling a more individualized health interventions and treatments.

胃癌为我国第二高发的恶性肿瘤，临床病例多为进展期且预后不良，5年生存率低于30%，因此若能找到有效的血液肿瘤标记物，进行胃癌的早期筛查、监测和预后评估将具有重要意义。循环肿瘤DNA（ctDNA）携带肿瘤特异性基因突变和表观基因改变，充分反应了肿瘤的遗传特征，有望成为新的无创肿瘤筛查和监测标记物。本研究拟依托已建立的胃癌队列，采用测序法和磁珠乳液扩增法检测ctDNA的胃癌驱动基因突变和靶基因甲基化情况，比较其在胃癌患者和对照间，不同程度胃粘膜病变患者间，同一胃癌患者术前和术后，复发前和复发后的差异，筛选出组间分布差异最大的若干ctDNA遗传特征组合。确定ctDNA遗传特征组合的预警价值，并联合其他流行病学危险因素和临床数据，构建发病风险的预测模型和预后评估模型，实现胃癌发病风险的个体化评估和高危复发患者的界定，为精准干预和精准治疗提供理论依据。

循环肿瘤DNA（ctDNA）携带肿瘤特异性基因突变和表观基因改变，充分反应了肿瘤的遗传特征，有望成为新的无创肿瘤筛查和监测标记物。本研究依托已建立的胃癌队列，重点检测了ctDNA的羟甲基化修饰情况，比较其在胃癌患者和对照间的差异。基于基因体羟甲基化差异基因构建的胃癌风险预测模型，该模型经过外部数据验证具有良好的效能，外验证AUC达到0.895，灵敏度和特异度分别为81.9%和90.2%，实现了胃癌发病风险的个体化评估和高危复发患者的界定。同时分析了肿瘤组织DNA的羟甲基化水平与胃癌患者临床特征和长期预后间的关系，发现DNA的羟甲基化水平降低时胃癌患者不良预后的独立危险因素。上述结果为下一步探索ctDNA的羟甲基化特征在胃癌早期发现、预后预测及复发监测中的应用价值提供了依据，也为胃癌的精准干预和精准治疗提供了理论依据。

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