Mucins in the Diagnosis and Prognosis of Pancreatic Diseases

描述（由申请人提供）：由于其无症状性质和缺乏早期检测方法，> 80%的胰腺癌（PC）患者在诊断时存在不可切除的原发性肿瘤伴远处转移。虽然胰腺癌的总体5年生存率令人沮丧，但据报道，在早期发现的较小肿瘤的结局明显更好。PC的缓慢发展与早期疾病患者更好的治疗反应相结合，强调了早期发现胰腺癌的必要性。虽然没有共识的诊断方法，早期发现PC，鉴于其罕见的患病率，有越来越多的协议，以针对高风险的个人进行早期诊断。家族性PC患者和胰腺囊性病变患者被认为是可能发生胰腺癌的两个明确定义的高危人群。胰腺囊性病变，早期被认为是罕见的，越来越多地被承认，由于越来越多的人正在接受诊断成像;然而，他们的确切患病率是未知的。这些囊性胰腺病变具有不同的恶性潜能：虽然粘液性囊性肿瘤（MCN）和导管内胰腺粘液性肿瘤（IPMN）发展为恶性病变的可能性很高，但浆液性囊性肿瘤（SCN）被认为是良性的。尽管迫切需要，准确区分高风险和低风险囊性病变是具有挑战性的，因为它们的症状和影像学相似性。虽然内镜超声（EUS）引导下细针穿刺（FNA）细胞学检查已成为术前评估不可或缺的一部分，但在实践中，50%-60%的此类分析在区分浆液性和粘液性病变方面不确定且不可靠。利用本课题组制备的抗MUC 4单克隆抗体8 G7，多项研究表明，细胞表面粘蛋白MUC 4是一种有前景的预后和诊断生物标志物。MUC 4表达在PanIN前体病变中逐渐增加，并且在EUS FNA中可检测到。该建议的中心假设是胰腺组织中MUC 4的检测与已经存在的胰腺癌或癌前病变的存在正相关，因此可以成为早期诊断和预测受这种致命疾病影响的患者预后的有力工具。 提出了两个具体目标。在目标1（I期）中，使用存档的FNA和匹配的切除标本，我们将证明我们有能力成功地确定MUC 4在胰腺囊性病变中的表达，并建立MUC 4表达可以预测隐匿性恶性肿瘤或癌前病变的发生，否则无法通过常规方法检测。未来的研究将在多中心试验中验证MUC 4免疫染色的意义，并确定MUC 4表达如何与实性/囊性胰腺疾病的临床结局相关。总体而言，该提案将作为一个平台，以确定MUC 4在胰腺囊性病变和PC背景下的临床决策中是否有潜在作用。

DESCRIPTION (provided by applicant): Due to its asymptomatic nature and lack of methods for early detection, > 80% of pancreatic cancer (PC) patients present with an unresectable primary tumor with distant metastasis at the time of diagnosis. While the overall 5 year survival rate of pancreatic cancer is dismal, significantly better outcomes have been reported for smaller tumors detected at an earlier stage. Slow development of PC in conjunction with the better curative response of patients with early disease underscore the need of early detection of pancreatic cancer. While there is no consensus on the diagnostic approaches for early detection of PC, in light of its rare prevalence, there is a growing agreement to target high-risk individual for early diagnosis. Individuals with familial PC and patients harboring cystic lesions in the pancreas are considered be the two well defined high-risk groups likely to develop pancreatic cancer. Pancreatic cystic lesions, earlier considered to be rare, are increasingly being recognized due to increased number of individuals being subjected to diagnostic imaging; however, their exact prevalence is unknown. These cystic pancreatic lesions have variable malignant potential: while mucinous cystic neoplasms (MCNs) and intraductal pancreatic mucinous neoplasms (IPMNs) have a high probability of developing into malignant lesions, serous cystic neoplasms (SCNs) are considered benign. Despite the critical need, accurate discrimination between high- and low-risk cystic lesions is challenging due to their symptomatic and radiographic similarities. Although cytologic examination of endoscopic ultrasound (EUS) guided fine needle aspirates (FNAs) has emerged as an indispensable part of presurgical evaluation, in practice, 50%-60% of such analyses are inconclusive and unreliable in discriminating between serous and mucinous lesions. Using anti-MUC4 monoclonal antibody 8G7 generated by our group several studies have established that cell surface mucin MUC4 is promising prognostic and diagnostic biomarker. MUC4 expression increases progressively in precursor PanIN lesions and is detectable in EUS FNAs. The central hypothesis of this proposal is that the detection of MUC4 in pancreatic tissues is positively correlated with the presence of already existing pancreatic cancer or precancerous lesions and thus could be a powerful tool for the early diagnosis and for predicting the prognosis of patients affected with this lethal disease. Two specific aims are proposed. In Aim 1 (Phase I) using archived FNAs and matched resected specimens, we will demonstrate our ability to successfully determine MUC4 expression in cystic pancreatic lesions and establish that MUC4 expression can predict the occurrence of occult malignancy or preneoplasatic lesions that are otherwise undetectable by conventional methods. Future studies will validate the significance of MUC4 immunostaining in a multi-center trial and determine how MUC4 expression correlates with the clinical outcome of the solid/cystic pancreatic diseases. Overall, the proposal will serve as a platform to determine if there is a potential role of MUC4 in clinical decision making in the context of pancreatic cystic lesions and PC.