Using markers to improve pancreatic cancer screening and surveillance

由于大多数胰腺癌患者表现为晚期疾病，因此需要进行胰腺筛查， 检测早期无症状的潜在可治愈病变。胰腺癌筛查（CAPS） 临床研究中，我们筛选了约600名患胰腺癌风险增加的个体， 家族史或基因突变标准。筛查可以识别癌前病变和胰腺癌， 但需要更好的循环和胰液标记物来帮助胰腺评估。胰液 在常规内镜超声检查期间从十二指肠收集的样本显示，该样本是 胰腺肿瘤的生物标志物和胰液分析可能是一种有用的诊断测试。因此，在本发明中， GNAS突变对IPMN是高度特异性的，在患有糖尿病的患者的果汁样品中特异性地检测到。 IPMN。KRAS突变通常不仅存在于胰腺炎患者的胰液中， 癌症，但在接受胰腺筛查的患者中，即使他们没有胰腺癌的证据， 通过影像学检查发现肿瘤。这些突变中的许多被认为是在PanIN中出现的，而PanIN不能被检测到。 胰腺影像学检查，因为这些病变非常小，不形成肿块。因此，胰液 分析有可能表明PanIN的存在。更有价值的是一个测试， 胰腺肿瘤的级别，因为在没有癌症的情况下，这通常是不可能确定的 而不分析切除的胰腺我们知道TP 53和SMAD 4突变出现在高级别的乳腺癌中， 在胰腺癌中发现TP 53和SMAD 4突变， 胰腺癌和高度异型增生患者的样本，而不是疾病对照组或低- 等级发育不良。为了进一步评估候选诊断标志物，我们提出：目标#1：确定 在胰液中检测到的突变作为胰腺癌标志物的诊断准确性， 癌前病变我们将使用新的nextgen测序方法来检测患者的突变， 胰腺癌、IPMN、慢性胰腺炎或正常胰腺。目的#2：评价循环标志物 作为早期发现胰腺癌的诊断测试。我们将评估ctDNA和外泌体标记。 目的#3：评价胰液和血清标志物作为检测PanIN-3和/或临床前 在接受胰腺筛查和监测的高风险个体中发生胰腺癌。我们将 建立一个珍贵样本的组织库，以帮助评估胰腺癌候选人 标记物，包括来自高风险受试者和PanIN-3病变的样本。

Since most patients with pancreatic cancer present with advanced disease, pancreatic screening is needed to detect asymptomatic early-stage potentially curable lesions. In our CAncer of the Pancreas Screening (CAPS) clinical studies we have screened ~600 individuals at increased risk of developing pancreatic cancer using family history or gene mutation criteria. Screening can identify precancerous lesions and pancreatic cancers, but better circulating and pancreatic juice markers are needed to aid in pancreatic evaluation. Pancreatic juice collected from the duodenum during routine endoscopic ultrasound reveals that this sample is a rich source of biomarkers of pancreatic neoplasia and the analysis of pancreatic juice could be a useful diagnostic test. Thus, GNAS mutations are highly specific for IPMNs are specifically detected in the juice samples of patients with IPMNs. KRAS mutations are commonly found not only in the pancreatic juice of patients with pancreatic cancer, but in patients undergoing pancreatic screening even when they do not have evidence of pancreatic neoplasia by imaging. Many of these mutations are thought to arise in PanIN, which are not detected by pancreatic imaging tests because these lesions are very small and do not form masses. Thus, pancreatic juice analysis has the potential to indicate the presence of PanIN. More valuable would be a test that would indicate the grade of pancreatic neoplasia since in the absence of cancer, this is usually not possible to determine without analyzing the resected pancreas. We know that TP53 and SMAD4 mutations emerge in high-grade dysplasia and invasive pancreatic cancer tumors and can find TP53 and SMAD4 mutations in pancreatic juice samples in patients with pancreatic cancer and high-grade dysplasia, not in disease controls or those with low- grade dysplasia. To further evaluate candidate diagnostic markers we propose: Aim #1: To determine the diagnostic accuracy of mutations detected in pancreatic fluid as markers of pancreatic cancer and precancerous lesions. We will use novel nextgen sequencing methods to detect mutations in patients with pancreatic cancer, IPMNs, chronic pancreatitis, or normal pancreata. Aim #2: To evaluate circulating markers as diagnostic tests for the early detection of pancreatic cancer. We will evaluate ctDNA and exosomal markers. Aim #3: To evaluate pancreatic fluid and serum markers as tests to detect PanIN-3 and/or pre-clinical pancreatic cancer among high-risk individuals undergoing pancreatic screening and surveillance. We will develop a tissue repository of precious samples to aid in the evaluation of candidate pancreatic cancer markers, including samples from high-risk subjects and PanIN-3 lesions.