Antibody bead array technology for diagnosis of pre-invasive pancreatic cancer

描述(由申请人提供)：成功的癌症筛查的一个关键组成部分是识别一个病变，对其进行干预将导致延长生存或治愈。IA期胰腺癌(最早可识别的病变，占所有胰腺癌的1%)患者的五年存活率约为35%。胰腺导管内乳头状黏液性肿瘤(IPMN)是一种囊性肿瘤，是胰腺癌唯一的放射学可识别的前驱病变，约占胰腺恶性肿瘤的20%-30%。目前的实验室、内窥镜和成像技术无法区分低风险(低级别异型增生)和高风险(高级别异型增生)的IPMN恶变。我们最近在高危IPMN患者的囊液中发现了差异表达的蛋白质(IL-1b、IL-5、IL-8、MUC-2、MUC-4)。我们假设囊液抗体珠阵列可以作为一种诊断工具来识别胰腺癌前囊性病变(IPMN)患者，这些患者有很高的恶变风险。在这项建议中，我们将把上述差异表达的蛋白质合并到抗体珠阵列中，我们已经在囊液分析中使用该抗体阵列来区分良性胰腺囊肿。抗体珠阵列分析将对经病理证实(切除)的低风险(低和中度不典型增生)和高风险(高级别不典型增生)IPMN患者的囊液进行分析。将比较低风险和高风险IPMN之间的差异蛋白表达，以评估异常增生的其他标志物。样本分类将被用来开发一个预测高度不典型增生的模型。这个模型是从手术获得的样本发展而来的，然后将在内窥镜获得的样本(内窥镜超声抽吸)上进行评估。开发一种区分低风险和高风险IPMN的术前测试，将使高风险病变的患者在基本无法治愈的疾病发展之前就被切除，并使低风险病变的患者能够避免手术，并节省他们胰腺切除术的体力、情感和经济成本。 公共卫生相关性：胰腺导管内乳头状黏液性肿瘤(IPMN)是胰腺癌的囊性前驱病变，从低度不典型增生演变到高度不典型增生再到癌。最近，我们从IPMN患者的囊液中发现了有希望的蛋白质生物标志物(MUC-2、MUC-4、IL-1b、IL-5、IL-8)，这些标志物在低危和高危病变中差异表达。在这项提案中，我们计划将这些生物标记物整合到我们以前在囊液分析中使用的抗体珠阵列中，并评估是否可以开发囊液分析来识别患有IPMN的患者，这些患者具有发展为胰腺癌的高风险。

DESCRIPTION (provided by applicant): A critical component to successful cancer screening is the identification of a lesion for which intervention will result in prolonged survival or cure. The five-year survival of patients with resected stage IA pancreas cancer (the earliest identifiable lesion and <<1% of all pancreatic cancer) is approximately 35%. Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are cystic tumors that represent the only radiographically identifiable precursor lesion of pancreatic cancer and represent approximately 20% - 30% of pancreatic malignancy. Current laboratory, endoscopic, and imaging technologies are unable to distinguish between IPMN that is at low-risk (low-grade dysplasia) or high-risk (high-grade dysplasia) of becoming malignant. We have recently identified differentially expressed proteins (IL-1b, IL-5, IL-8, MUC-2, MUC-4) in the cyst fluid of patients with high-risk IPMN. We hypothesize that antibody bead array of cyst fluid can be utilized as a diagnostic tool to identify patients with pre-malignant cysts of the pancreas (IPMN) that are at high risk for progressing to malignancy. In this proposal we will incorporate the differentially expressed proteins noted above into an antibody bead array that we have used in cyst fluid analysis for the discrimination of benign pancreatic cysts. Antibody bead array analysis will be performed on cyst fluid from patients with pathologically proven (resected) low-risk (low and moderate grade dysplasia) and high-risk (high-grade dysplasia) IPMN. Differential protein expression will be compared between low-risk and high-risk IPMN to evaluate for additional markers of dysplasia. Sample classification will be used to develop a model for predicting high-grade dysplasia. This model, developed from operatively obtained samples, will then be evaluated on samples obtained endoscopically (endoscopic ultrasound aspiration). Development of a preoperative test to discriminate between low-risk and high-risk IPMN would allow patients with high-risk lesions to be resected prior to the development of an essentially incurable disease, and enable patients with low-risk lesions to avoid operation and spare them the physical, emotional, and financial costs of pancreatectomy. PUBLIC HEALTH RELEVANCE: Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are radiographically identifiable cystic precursor lesions of pancreatic cancer that evolve from low-grade dysplasia to high-grade dysplasia to carcinoma. Recently we have identified promising protein biomarkers (MUC-2, MUC-4, IL-1b, IL-5, IL- 8) from the cyst fluid of patients with IPMN that are differentially expressed in low-risk and high-risk lesions. In this proposal we plan to incorporate these biomarkers into an antibody bead array that we have previously utilized in cyst fluid analysis and assess whether a cyst fluid assay can be developed to identify patients with IPMN who are at high-risk of developing pancreatic cancer.