Longitudinal Proteomic and Metabolomic Predictors of Pancreatic Cyst Malignant Progression and Early Stage Pancreatic Cancer

项目概要/摘要 胰腺导管腺癌（PDAC）的预后很差，主要是由于其诊断较晚。关键要坚持 识别早期PDAC及其前体。导管内乳头状粘液性肿瘤就是这样一种前兆 （IPMN），胰腺囊肿的一种。国际共识指南建议切除IPMN， 恶性风险和监测IPMN无手术指征。根据放射学/临床结果， 指南在区分良性和恶性IPMN方面的特异性令人沮丧， 预测IPMN恶性进展。目前迫切需要鉴定出能够预测肿瘤恶性进展的生物标志物。 “低风险”IPMN。拟议研究的主要目的是鉴定和验证蛋白质， 代谢物特征及其纵向变化，可以区分IPMN恶性进展， 检测早期PDAC。在初步数据的支持下，我们的中心假设是， 血浆和/或胰腺囊肿液中的这些特征的轨迹预测IPMN恶性 进展和早期PDAC。具体目标：1。研究血浆和囊液水平和轨迹 蛋白质组学生物标志物和代谢组学特征用于预测IPMN恶性进展， 前瞻性监测队列。1A：胰腺囊肿液的整体蛋白质组学和代谢组学研究， 将对160名IPMN手术患者进行鉴定，以确定与高级别 入侵性IPMN 1B：从1A和6种蛋白质（THBS 2、PGE 2、LRG 1、TIMP 1、C1 RL、& 在我们的初步研究中发现的PTPRJ）将在连续血浆（n=3）和囊液（n=~2.5）中测量 500例IPMN患者的样本进行监测。1C：从1A和4份血浆中鉴别出的主要代谢物 在我们的R21研究中，与IPMN发育不良等级相关的代谢物将在1B人群中定量。的 将评价1B和1C中测定的蛋白质和代谢物的水平和轨迹与IPMN的关系 恶性进展1D：将从蛋白质构建IPMN恶性进展的风险预测模型 以及在1B和1C、CA 19-9和临床/成像特征中鉴别和验证的代谢物。2.评价 血浆蛋白质组学生物标志物和代谢组学特征的水平和轨迹， 在PLCO队列中嵌套的符合PRoBE的病例对照研究中的PDAC期。2A：1A中鉴定的蛋白质 1B中列出的6种生物标志物将在来自242名患者的系列诊断前血浆样本（n=最多3）中进行测量 PDAC病例（包括80例早期病例）和242例匹配对照。2B：在2A人群中， 在我们的试验中，从1A、1C中描述的4种代谢物和预测早期PDAC的5种代谢物中鉴定出 研究将确定。2C：将从蛋白质开发早期PDAC的风险预测模型 以及在2A和2B、CA 19-9和临床/成像特征中鉴定的代谢物。我们的预期结果将允许 临床医生在进展为浸润性癌症之前及时切除具有高恶性潜能的IPMN， 避免不必要的手术。检测早期PDAC将大大提高患者的生存率。

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) has a dire prognosis mainly due to its late diagnosis. It is vital to identify early-stage PDAC and its precursors. One such precursor is intraductal papillary mucinous neoplasm (IPMN), a type of pancreatic cyst. International consensus guidelines recommend resection of IPMN with high malignancy risk and surveillance of IPMN without surgical indications. Based on radiologic/clinical findings, the guidelines have a dismal specificity for discerning benign from malignant IPMN and a poor accuracy of predicting IPMN malignant progression. It is urgent to identify biomarkers that predict malignant progression of presumed “low-risk” IPMN. The primary objective of the proposed study is to identify and validate protein and metabolite signatures and their longitudinal changes which can discriminate IPMN malignant progression and detect early-stage PDAC. Supported by preliminary data, our central hypothesis is that the levels and trajectories of such signatures in plasma and/or pancreatic cyst fluid are predictive of IPMN malignant progression and early-stage PDAC. Specific Aims: 1. Investigate plasma and cyst fluid levels and trajectories of proteomic biomarkers and metabolomics signatures for prediction of IPMN malignant progression in a prospective surveillance cohort. 1A: A global proteomics and metabolomics study of pancreatic cyst fluid in 160 IPMN surgical patients will be conducted to identify proteins and metabolites associated with high-grade and invasive IPMN. 1B: Top proteins identified from 1A and 6 proteins (THBS2, PGE2, LRG1, TIMP1, C1RL, & PTPRJ) discovered in our preliminary studies will be measured in serial plasma (n=3) and cyst fluid (n=~2.5) samples from 500 IPMN patients under surveillance. 1C: Top metabolites identified from 1A and 4 plasma metabolites correlated with IPMN dysplasia grade in our R21 study will be quantified in the 1B population. The levels and trajectories of proteins and metabolites measured in 1B and 1C will be evaluated in relation to IPMN malignant progression. 1D: A risk prediction model for IPMN malignant progression will be built from proteins and metabolites identified and validated in 1B and 1C, CA 19-9, and clinical/imaging features. 2. Evaluate levels and trajectories of plasma proteomic biomarkers and metabolomics signatures for detection of early- stage PDAC in a PRoBE-compliant case-control study nested in the PLCO cohort. 2A: proteins identified in 1A and 6 biomarkers listed in 1B will be measured in serial prediagnostic plasma samples (n=up to 3) from 242 PDAC cases (incl. 80 early-stage cases) and 242 matched controls. 2B: In the 2A population, top metabolites identified from 1A, 4 metabolites described in 1C, and 5 metabolites predicting early-stage PDAC in our pilot studies will be determined. 2C: A risk prediction model for early-stage PDAC will be developed from proteins and metabolites identified in 2A and 2B, CA 19-9, and clinical/imaging features. Our expected results will allow clinicians to timely resect IPMNs with high malignant potential before progression to invasive cancer, while avoiding unnecessary surgeries. Detecting early-stage PDAC will substantially increase patient survival.