microRNAs as novel Biomarkers for Pancreatic Ductal Adenocarcinoma
Principal Investigator: Murray Korc
Abstract: 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.
Funding Period: 2008-08-01 - 2010-07-31
more information: NIH RePORT
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Department of Medicine, Dartmouth Hitchcock Medical Center, Hanover, NH, USA
Methods Mol Biol 980:43-59. 2013....
- Analysis of microRNAs in pancreatic fine-needle aspirates can classify benign and malignant tissuesAnna E Szafranska
Asuragen Inc, Austin, TX, USA
Clin Chem 54:1716-24. 2008....
- Fluorescence-based codetection with protein markers reveals distinct cellular compartments for altered MicroRNA expression in solid tumorsLorenzo F Sempere
Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA
Clin Cancer Res 16:4246-55. 2010..This ISH method was implemented to be compatible with routine clinical immunohistochemical (IHC) assays to enable the detection of miRNAs and protein markers in the same tissue section for colocalization and functional studies...
- MicroRNA-10b expression correlates with response to neoadjuvant therapy and survival in pancreatic ductal adenocarcinomaMeir Preis
Department of Medicine and Pathology, Dartmouth Hitchcock Medical Center, Lebanon, USA
Clin Cancer Res 17:5812-21. 2011..MicroRNAs (miRNA) are noncoding regulatory RNAs involved in initiation and progression of human cancers. In this study, we sought to determine whether miR-10b could serve as a biomarker for PDAC...