Mucins in the Diagnosis and Prognosis of Pancreatic Diseases

描述（由申请人提供）：由于其无症状性和缺乏早期发现方法，bbb80 %的胰腺癌（PC）患者在诊断时存在不可切除的原发肿瘤并远处转移。虽然胰腺癌的总体5年生存率很低，但据报道，早期发现的较小肿瘤的预后明显更好。胰腺癌的缓慢发展和早期疾病患者较好的治疗反应强调了早期发现胰腺癌的必要性。尽管对于早期发现前列腺癌的诊断方法尚无共识，但鉴于其罕见的患病率，越来越多的人同意针对高危个体进行早期诊断。家族性PC患者和胰腺囊性病变患者被认为是两个明确定义的可能发展为胰腺癌的高危人群。胰腺囊性病变，早期被认为是罕见的，由于越来越多的个体接受诊断成像，越来越多地被认识到；然而，它们的确切患病率尚不清楚。这些胰腺囊性病变具有不同的恶性潜能：粘液囊性肿瘤（MCNs）和导管内胰腺粘液瘤（IPMNs）发展为恶性病变的概率很高，浆液性囊性肿瘤（SCNs）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，因为它们的症状和放射学的相似性。虽然内镜超声（EUS）引导下的细针抽吸（FNAs）细胞学检查已成为手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黏液性病变方面是不确定和不可靠的。利用本课组制备的抗MUC4单克隆抗体8G7，多项研究证实细胞表面黏液蛋白MUC4是一种有前景的预后和诊断生物标志物。MUC4表达在PanIN前体病变中逐渐增加，在EUS FNAs中可检测到。本研究的中心假设是胰腺组织中MUC4的检测与已经存在的胰腺癌或癌前病变呈正相关，因此可能是早期诊断和预测这种致命疾病患者预后的有力工具。

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.