Mutation-Specific p53 Antibodies as Biomarkers of Pancreatic Cancer

描述（由申请人提供）：胰腺癌仍然是一种高致死性疾病，没有确定的生物标志物或早期检测的筛查策略。TP 53的体细胞突变，主要是在蛋白质的DNA结合核心区域，导致蛋白质稳定和自身抗体（AAb）的产生。使用一种新的蛋白质展示和血清IgG检测方法，我们已经检测到P53-AAb野生型（WT）蛋白在浆液性卵巢癌中具有中等的敏感性和高特异性，包括假阴性CA 125病例的子集。在卵巢癌中，我们检测到p53-AAb水平在临床诊断前9个月开始升高，并且由于胰腺癌具有与浆液性卵巢癌相似的早期p53突变，我们预测这些标志物将存在于胰腺癌患者血清中。由于AAb是由突变型p53诱导产生的，因此针对突变型p53的AAb可能会改善检测。我们开发了一种蛋白质微阵列，表达实体瘤中存在的68种最常见的p53突变。在这里，我们建议，以确定频率WT和突变体特异性p53-AAb，在早期和晚期胰腺癌患者的血清中。我们将通过IHC将p53-AAb检测与原发性和转移性肿瘤p53表达以及TP 53突变状态相关联。 公共卫生相关性：目前还没有确定的生物标志物用于胰腺癌的早期检测，胰腺癌仍然是一种高度致命的疾病，几乎总是检测到手术切除太晚。该项目的目标是确定测量p53自身抗体的血液生物标志物，以特异性检测早期胰腺癌。

DESCRIPTION (provided by applicant): Pancreatic cancer remains a highly lethal disease, with no established biomarkers or screening strategy for early detection. Somatic mutation in TP53, primarily in the DNA-binding core region of the protein, results in protein stabilization and autoantibody (AAb) generation. Using a novel method of protein display and detection of serum IgG, we have detected P53-AAb to wild-type (WT) protein in serous ovarian cancer with moderate sensitivity and high specificity, including a subset of cases with false-negative CA 125. In ovarian cancer, we detected rising p53-AAb levels starting 9 months prior to clinical diagnosis, and since the pancreatic cancer has similar, early p53 mutations as serous ovarian cancer, we predict these markers will be present in pancreatic cancer patient sera. Since the AAb were induced by mutated p53, AAb to forms of mutant p53 may improve the assay. We developed a protein microarray expressing the 68 most common p53 mutations that are present in solid tumors. Here, we propose to determine the frequency of WT and mutant-specific p53-AAb, in sera from patients with early and late-stage pancreatic cancers. We will correlate p53-AAb detection with primary and metastatic tumor p53 expression by IHC, and with TP53 mutation status. PUBLIC HEALTH RELEVANCE: There are currently no established biomarkers for the early detection of pancreatic cancer, which remains a highly lethal disease that is almost always detected too late for surgical resection. The goal of this project is to identify blood-based biomarkers measuring autoantibodies to p53 to specifically detect early-stage pancreatic cancer.