microRNAs as novel Biomarkers for Pancreatic Ductal Adenocarcinoma

microRNA 作为胰腺导管腺癌的新型生物标志物

• 批准号: 7663739
• 负责人: Murray Korc
• 金额: $ 14.39万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663739
• 关键词: Adult; Benign; Biological Markers; Cancer Biology; Cancer Etiology; Cells; Cessation of life; Clinical; Desmoplastic; Development; Diagnosis; Diagnostic; Ductal; Early Diagnosis; Elements; Endoscopic Ultrasonography; Excision; Fine needle aspiration biopsy; Formalin; Functional RNA; Gene Expression; Genes; Genetic Transcription; Goals; Heterogeneity; Human; In Situ Hybridization; Incidence; Individual; Inflammatory; Investigation; Lesion; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Messenger RNA; Metaplasia; Methodology; MicroRNAs; Molecular; Monitor; Operative Surgical Procedures; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Paraffin Embedding; Patients; Pilot Projects; Procedures; Progress Review Group; Proteins; Protocols documentation; Regulator Genes; Reporting; Risk Factors; Sampling; Sensitivity and Specificity; Solid Neoplasm; Spatial Distribution; Specimen; Staging; Suspension substance; Suspensions; Techniques; Tissues; Ultrasonography; United States; base; cancer cell; cell preparation; cell type; chronic pancreatitis; clinical application; high risk; improved; intraepithelial; leukemia; mortality; neoplastic cell; novel; novel therapeutics; outcome forecast; public health relevance; sample fixation; tissue processing; tumor

DESCRIPTION (provided by applicant): Human pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in adults in the United States. As underscored by the NCI-sponsored Report of the Pancreatic Cancer Progress Review Group there is a tremendous need to develop novel biomarkers and novel therapeutic strategies. Thus, it is important to determine whether there are informative molecular biomarkers that can be identified for diagnostic purposes. This proposal focuses on microRNAs (miRNAs) as potential biomarkers in PDAC. miRNAs are a recently- discovered class of short non-coding RNA genes, which act as post-transcriptional negative regulators of gene expression. Altered expression of specific subsets of miRNAs has been linked to different types of leukemias and solid tumors, and they appear to have potential clinical value as biomarkers for early detection, diagnosis and/or prognosis. Moreover, their small size makes them less sensitive than messenger RNAs (mRNAs) of protein-encoding genes to degradation often associated with processing of tissue for formalin-fixation and paraffin-embedding (FFPE) or cell preparation obtained by endoscopic ultrasound-guided (EUS) fine needle aspiration (FNA). Thus, miRNAs may be more suitable biomarkers than mRNAs for expression characterization in archival tissue specimens and FNA cell samples obtained from the pancreas. Our preliminary studies (and/or reports from other groups) have linked a small subset of miRNAs to PDAC. In addition, we have implemented a miRNA in situ hybridization (ISH) protocol that permits the quantification of miRNA expression within individual cells in paraffin-embedded pancreatic tissue or in cell suspension. This pioneering technique will allow us to evaluate whether changes of miRNA expression occur within the cancer cells in PDAC and/or within the ad- joining stromal and parenchymal elements, and whether these changes are already manifested at early stages of malignancy such as pancreatic intraepithelial lesions. Here, we propose to conduct a thorough investigation aimed at: 1) Identifying the best subset of miRNAs to discriminate PDAC from benign lesions and chronic pancreatitis; 2) Assessing the clinical value of this selected subset in a sample of 150 archival patient cases; and 3) Implementing ISH methodology for potential clinical application of miRNAs as early detection or diagnostic biomarkers on FNA samples. PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy in which mortality virtually equals incidence, yet for which there are no early diagnostic markers. miRNAs are a novel class of regulatory RNAs with great importance in cancer biology. We propose that changes in miRNA expression are linked to the initiation and/or progression of PDAC, and that characterization of these changes will provide the basis for assessing in a clinical setting the value of these miRNAs as novel biomarkers for early detection and diagnosis of PDAC when used in conjunction with endoscopic ultrasonography.

描述（由申请方提供）：人胰腺导管腺癌（PDAC）是美国成人癌症死亡的第四大原因。正如NCI-sponsored Report of the Pancreatic Cancer Progress Review Group所强调的那样，开发新的生物标志物和新的治疗策略是非常必要的。因此，重要的是要确定是否有信息分子生物标志物，可以确定用于诊断目的。该建议的重点是microRNAs（miRNAs）作为PDAC的潜在生物标志物。miRNA是近年来发现的一类短的非编码RNA基因，其作为基因表达的转录后负调控因子。miRNAs的特定亚群的表达改变与不同类型的白血病和实体瘤有关，并且它们似乎具有作为早期检测、诊断和/或预后的生物标志物的潜在临床价值。此外，它们的小尺寸使得它们比蛋白质编码基因的信使RNA（mRNA）对降解不太敏感，所述降解通常与用于福尔马林固定和石蜡包埋（FFPE）的组织处理或通过内窥镜超声引导（EUS）细针抽吸（FNA）获得的细胞制备相关。因此，对于从胰腺获得的存档组织样本和FNA细胞样本中的表达表征，miRNA可能是比mRNA更合适的生物标志物。我们的初步研究（和/或来自其他小组的报告）将一小部分miRNA与PDAC联系起来。此外，我们已经实施了一个miRNA原位杂交（ISH）协议，允许量化的miRNA表达在石蜡包埋的胰腺组织或细胞悬液中的单个细胞内。这项开创性的技术将使我们能够评估miRNA表达的变化是否发生在PDAC中的癌细胞内和/或在相邻的基质和实质成分内，以及这些变化是否已经在恶性肿瘤的早期阶段如胰腺上皮内病变中表现出来。在这里，我们建议进行一项彻底的研究，旨在：1）确定最佳的miRNAs子集，以区分PDAC良性病变和慢性胰腺炎; 2）评估150例存档患者病例样本中所选子集的临床价值; 3）实施ISH方法，用于miRNAs作为FNA样本早期检测或诊断生物标志物的潜在临床应用。公共卫生关系：胰腺导管腺癌（PDAC）是一种致命的恶性肿瘤，死亡率几乎等于发病率，但没有早期诊断标志物。miRNAs是一类在肿瘤生物学中具有重要意义的新型调控RNA。我们认为miRNA表达的变化与PDAC的发生和/或进展有关，并且这些变化的特征将为在临床环境中评估这些miRNA作为早期检测和诊断PDAC的新型生物标志物的价值提供基础。