Validation of a Mouse Model of Pancreatic Carcinogenesis
Summary
The primary aim of this study is to determine if mutations of BRCA1 and BRCA2 result in different precancerous pathways to pancreatic ductal adenocarcinoma (PDAC), as suggested in our validated mouse model. Genomic DNA will be isolated on normal tissue obtained from patients who underwent pancreatic resection for PDAC, intraductal papillary mucinous neoplasm (IPMN) or mucinous cystic neoplasm (MCN). Tissue will be examined for the three most common founder mutations in Ashkenazi Jews. In the cases in which BRCA1 or BRCA2 mutations are found, heterozygote normal and abnormal tissue will be examined to look for mutations in the other BRCA1 or BRCA2 allele. The interaction between other cancer causing genes with BRCA1/2 will also be evaluated by comparing the sequences of the other genes in pre-cancerous lesions.
We hypothesize that BRCA1- and BRCA2-mediated pancreatic ductal adenocarcinoma progresses through the PanIN route, as seen in both BRCA1 and BRCA2 murine models of pancreatic cancer. We further hypothesize that BRCA1 mutations may enable an additional pre- neoplastic pathway through MCN, and that IPMN may embody yet another pre- neoplastic pathway.
Description
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death from malignancy in the United States. Several gene mutations and cancer syndromes have been identified that are found in greater frequency in individuals with PDAC, including the breast ovary cancer syndrome (BRCA1 and BRCA2 mutations). We have recently generated mouse models of pancreatic cancer in which we found that deletions of either BRCA1 or BRCA2 cooperate with K-ras activation and p53 mutations to increase the rate of tumorigenesis via accelerated progression of Pancreatic Intraepithelial Neoplasia (PanIN). However, only BRCA1 deletions were associated with the development of concomitant Mucinous Cystic Neoplasms (MCNs), suggesting potentially distinct pathways for BRCA1- and BRCA2-mediated tumorigenesis in the pancreas. Our primary aim is to determine if germline mutations of BRCA1 and BRCA2 result in different pre-neoplastic pathways to pancreatic cancer, as in our murine model. Genomic DNA will be isolated on normal tissue obtained from patients who underwent pancreatic resection for pancreatic cancer, IPMN or MCN. Tissue will be genotyped for the three most common founder mutations in Ashkenazi Jews. In the cases in which BRCA1 or BRCA2 mutations are found, heterozygote normal and abnormal tissue will be microdissected to look for loss of heterozygosity at the BRCA1 or BRCA2 allele. Our secondary aim is to evaluate the interaction of p53 and Kras with BRCA1 and BRCA2 by sequencing p53 and Kras in PanIN as compared to IPMN and MCN lesions.
Study Design
Observational Model: Cohort, Time Perspective: Retrospective
Conditions
Pancreatic Cancer
Location
Columbia University Medical Center
New York
New York
United States
10032
Status
Recruiting
Source
Columbia University
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT01103128
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Pancreatic Neoplasms
Tumors or cancer of the PANCREAS. Depending on the types of ISLET CELLS present in the tumors, various hormones can be secreted: GLUCAGON from PANCREATIC ALPHA CELLS; INSULIN from PANCREATIC BETA CELLS; and SOMATOSTATIN from the SOMATOSTATIN-SECRETING CELLS. Most are malignant except the insulin-producing tumors (INSULINOMA).
Pancreatic Stellate Cells
Star-shaped, myofibroblast-like cells located in the periacinar, perivascular, and periductal regions of the EXOCRINE PANCREAS. They play a key role in the pathobiology of FIBROSIS; PANCREATITIS; and PANCREATIC CANCER.
Pancreatic Polypeptide
A 36-amino acid pancreatic hormone that is secreted mainly by endocrine cells found at the periphery of the ISLETS OF LANGERHANS and adjacent to cells containing SOMATOSTATIN and GLUCAGON. Pancreatic polypeptide (PP), when administered peripherally, can suppress gastric secretion, gastric emptying, pancreatic enzyme secretion, and appetite. A lack of pancreatic polypeptide (PP) has been associated with OBESITY in rats and mice.
Pancreatic Extracts
Extracts prepared from pancreatic tissue that may contain the pancreatic enzymes or other specific uncharacterized factors or proteins with specific activities. PANCREATIN is a specific extract containing digestive enzymes and used to treat pancreatic insufficiency.
Trypsin Inhibitor, Kazal Pancreatic
A pancreatic trypsin inhibitor common to all mammals. It is secreted with the zymogens into the pancreatic juice. It is a protein composed of 56 amino acid residues and is different in amino acid composition and physiological activity from the Kunitz bovine pancreatic trypsin inhibitor (APROTININ).
Clinical Trials
Local Invasion of Pancreatic Cancer
Pancreatic cancer often spreads through local invasion into local structures, including fat, blood vessels, nerves, and nearby organs (stomach, duodenum, spleen, bile duct). Local microsco...
Low Dose Vaccine Study for Surgically Resected Pancreatic Cancer
To assess the response for subjects with pancreatic cancer that have undergone surgical resection and treatment with a vaccine given with or without chemotherapy and chemoradiation.
In suspecting pancreatic cancer, dynamic phase pancreatic CT is the most effective tool in diagnosis and staging. In addition, magnetic resolution image, endoscopic ultrasonography, endosc...
Pancreatic And Gastrointestinal Tumor Registry and Tissue Collection
The purpose of the study is to collect pancreatic tissue, blood and urine from adults to study pancreatic abnormalities.
INST 0603C Patients With Unresectable/Metastatic Pancreatic Cancer Treated in the UNM Cancer
Chart Review of patients with pancreatic cancer treated with combination of irinotecan, oxaliplatin and cetuximab.
PubMed Articles
Expression of A20 is reduced in pancreatic cancer tissues.
A20 protein plays essential roles in tumorigenesis, but its value for diagnosis of pancreatic cancer remains unclear. Our aim was to determine whether A20 is a potential biomarker for the diagnosis of...
Understanding pancreatic cancer genomes.
Pancreatic cancer is the fourth leading cause of cancer death in our society, with a mortality that virtually parallels its incidence, a median survival of
New insights into pancreatic cancer-induced paraneoplastic diabetes.
Up to 85% of patients with pancreatic cancer have diabetes or hyperglycaemia, which frequently manifests as early as 2-3 years before a diagnosis of pancreatic cancer. Conversely, patients with new-on...
Pancreatic cancer: Are pancreatic cysts a risk factor for pancreatic cancer?
Pancreatic cancer is the fourth leading cause of cancer death in the United States. Risk factors for pancreatic cancer are smoking, family history, chronic pancreatitis, and diabetes. There is controv...
