基因型肿瘤标志物ctDNA用于胰腺癌早期诊断及预后评价的基础与临床研究

The 5-year survival time of pancreatic adenocarcinoma (PDAC) is around 6%. Surgery is the main treatment protocol. However, some modified radical operation and extended radical resection could not improve the prognosis. In this situation, early diagnosis and early clinical intervention would be important to prolong life-span of patients with PDAC. Nowadays, Common blood circulating biomarker like CA199 could not guide prognosis and predict prognosis efficiently. So how to improve the way of early diagnosis is still one of the tough issues today. Circulating tumor DNA (ctDNA), which could be detected in human blood, has been used as a new biomarker in diagnosis of lung cancer and breast cancer. This gene diagnosis approach has higher disease specificity, higher sensitivity and specificity even at low concentration. The way to obtain ctDNA from blood is easy, so ctDNA will be an ideal approach for early diagnosis of PDAC. In this subject, we will collect the blood and tissue samples of patients with pancreatic cancer and their clinical data. We will check the gene mutations of ctDNA in blood through genomics techniques like next generation sequencing. We will compare these positive genes mutations in ctDNA with those that in pancreatic tissues. In addition, gene mutations and clinical data such as TNM staging and survival time will be analyzed. Compared with that of CA199 biomarker, the efficiency of ctDNA as a new diagnostic biomarker for pancreatic adenocarcinoma will be evaluated. A gene database of pancreatic cancer in West China and a standard operation procedure of cancer research will also be constructed.

胰腺导管腺癌为常见消化系统恶性肿瘤，五年生存期仅6%，外科手术仍是治疗胰腺癌的主要手段，但各种改良及扩大根治术并不能提高中晚期患者生存期，资料显示早诊早治具有重要临床意义，现有诊断方法已不能满足临床需求，故提高胰腺癌早期诊断水平是胰腺癌攻坚的重点及难点。患者循环血中肿瘤DNA（ctDNA）作为新型肿瘤标志物在乳腺癌、肺癌等肿瘤中的逐步应用，证实其具有特异度高、低浓度下敏感度强等特点，且检测便捷，使其可能成为胰腺癌早期诊断的理想方法。项目根据胰腺癌患者收治流程搜集临床病例资料，采集血液及组织标本，通过基因组学下一代基因测序等技术手段，检测患者循环血中ctDNA与胰腺癌组织基因突变的一致性，分析阳性突变基因与疾病分期和预后间的关系，与常规肿瘤标志物对比评估ctDNA作为新一代肿标用于胰腺癌早期诊断的临床价值，建立本中心基因诊断研究胰腺癌的标准作业程序、研究模式，完善地区胰腺癌患者基因数据库。

胰腺癌是一种常见的、肿瘤相关死亡率高的恶性消化器官肿瘤。早期诊断和早期手术治疗能使患者获益。该项目主要研究了胰腺癌肿瘤基因突变情况及与预后的关系，并进一步验证了基因表观修饰甲基化与5羟甲基化在胰腺癌中的特征分布。研究结果提示胰腺癌中确实存在基因突变，该队列中的基因突变结果与目前国内外研究一致，最常见的突变基因分别是KRAS（88%），Tp53（72%），CDKN2A（27%）、ARID1A（21%）、SMAD4（22%）。所有突变位点共计555个。96%的样本中出现了RTK-RAS通路改变、73%的样本中出现了TP53通路的改变、36%的样本中出现了TGF-beta通路的改变、32%的样本中出现了细胞周期通路的改变、11%的样本中出现了NOTCH通路的改变。死亡组胰腺癌患者出现TP53、TGFBR2、ACVR1B、NOTCH1突变的风险是存活组胰腺癌患者的3.23、3.74、4.2、3.03倍。研究还发现基于优化的机器学习算法得到的24个5mC诊断标志物与27个5hmC标志物整合，建立了共51个变量的双组学诊断模型。在验证集数据中模型预测灵敏度=93.8%，特异性=95.5%，AUC=0.997，具有有良好的灵敏度与特异性。. 本研究紧密围绕恶性肿瘤早期癌变的基因表观修饰分子可视化识别检测，发现新的诊断敏感度、特意度高、价格较合宜的肿瘤标志物，易于未来临床开发应用，建立临床信息、影像、病理特征与分子表征之间的整合用于胰腺癌早期诊断和鉴别诊断评估。因此，本研究无论从理论上还是临床应用上均具有创新性和实用性。

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