Mutation-Specific p53 Antibodies as Biomarkers of Pancreatic Cancer

描述(申请人提供)：胰腺癌仍然是一种高度致命的疾病，没有建立生物标记物或早期发现的筛查策略。TP53的体细胞突变，主要发生在蛋白质的DNA结合核心区，导致蛋白质稳定和自身抗体(AAB)的产生。应用一种新的蛋白展示和血清免疫球蛋白检测方法，我们检测了卵巢浆液性癌中P53-AAB对野生型(WT)蛋白的中等敏感性和高特异性，包括CA125假阴性的一组病例。在卵巢癌中，我们在临床诊断前9个月检测到P53-AAB水平上升，由于胰腺癌与浆液性卵巢癌具有相似的早期P53突变，我们预测这些标记物将出现在胰腺癌患者血清中。由于AAB是由突变的P53诱导的，因此将AAB转化为突变型P53可能会提高检测的效率。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，我们建议测定早期和晚期胰腺癌患者血清中WT和突变型P53-AAB的频率。我们将P53-AAB的检测与原发癌和转移性肿瘤的P53表达以及与TP53突变状态相关联。

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.