Validation of a Mouse Model of Pancreatic Carcinogenesis
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.
|Study Design:||Observational Model: Cohort
Time Perspective: Retrospective
|Official Title:||BRCA1 and BRCA2 Genetic Mutations in Mucinous Versus Nonmucinous Precursor Lesions of the Pancreas: Validation of a Mouse Model of Pancreatic Carcinogenesis|
- BRCA1 vs. BRCA2 mutations [ Time Frame: 1 year ]The primary aim is to determine if germline mutations of BRCA1 and BRCA2 result in different pre-neoplastic pathways to pancreatic cancer, as seen 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.
- Interaction of other cancer genes with BRCA1 and BRCA2 [ Time Frame: 1 year ]The secondary aim is to evaluate the interaction of p53 and K-ras with BRCA1 and BRCA2 by sequencing p53 and K-ras in PanIN as compared to IPMN and MCN lesions.
Biospecimen Retention: Samples With DNA
- Peripheral Blood Specimens: Three tubes of blood will be collected from each study participant. Two tubes will be EDTA-whole blood and one tube will be serum. Each tube will contain ~4-5 ml. A portion of the blood will be utilized to extract white blood cells that will be immortalized by EBV infection.
- Archived Fixed Tissue Samples: Tissue blocks from surgery performed at CUMC or elsewhere, will be requested after obtaining consent for study participation.
- Fresh Tissue Collection: At the time of surgery for tumor resection, tumor and adjacent normal tissue will be requested from the Pathology Department. At the time of endoscopy, aspirated fluid or biopsied tissue will be requested. No additional tissue will be resected beyond that required for surgical or endoscopic management.
- Genetic Testing: All genetic testing will be performed in a research laboratory. Test results from research laboratories will not be disclosed to patients.
|Study Start Date:||March 2009|
|Study Completion Date:||May 2013|
|Primary Completion Date:||May 2013 (Final data collection date for primary outcome measure)|
Please refer to this study by its ClinicalTrials.gov identifier: NCT01103128
|United States, New York|
|Columbia University Medical Center|
|New York, New York, United States, 10032|
|Principal Investigator:||Wendy K Chung, MD||Columbia University|