Validation of a Mouse Model of Pancreatic Carcinogenesis

The recruitment status of this study is unknown because the information has not been verified recently.
Verified July 2012 by Columbia University.
Recruitment status was  Recruiting
Sponsor:
Information provided by (Responsible Party):
Wendy K. Chung, Columbia University
ClinicalTrials.gov Identifier:
NCT01103128
First received: April 12, 2010
Last updated: July 2, 2012
Last verified: July 2012
  Purpose

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.


Condition
Pancreatic Cancer

Study Type: Observational
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

Resource links provided by NLM:


Further study details as provided by Columbia University:

Primary Outcome Measures:
  • BRCA1 vs. BRCA2 mutations [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Interaction of other cancer genes with BRCA1 and BRCA2 [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    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.

Estimated Enrollment: 450
Study Start Date: March 2009
Estimated Study Completion Date: May 2013
Estimated Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

All subjects have a tissue-confirmed diagnosis of pancreatic adenocarcinoma, MCN or IPMN and underwent surgical resection for pancreatic adenocarcinoma, MCN or IPMN at Columbia-Presbyterian Medical Center.

Criteria

Inclusion Criteria:

  • Tissue-confirmed diagnosis of pancreatic adenocarcinoma, MCN, or IPMN.
  • Underwent surgical resection for pancreatic adenocarcinoma, MCN, or IPMN.

Exclusion Criteria:

  • Unwilling to provide informed consent.
  • Under the age of 18.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01103128

Contacts
Contact: Wendy K Chung, MD wkc15@columbia.edu
Contact: Reena Shakya, MD rs566@columbia.edu

Locations
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Wendy K Chung, MD       wkc15@columbia.edu   
Principal Investigator: Wendy K Chung, MD         
Sponsors and Collaborators
Columbia University
Investigators
Principal Investigator: Wendy K Chung, MD Columbia University
  More Information

No publications provided

Responsible Party: Wendy K. Chung, Assistant Professor of Pediatrics, Molecular Genetics, Columbia University
ClinicalTrials.gov Identifier: NCT01103128     History of Changes
Other Study ID Numbers: AAAE0097, AAAE0097
Study First Received: April 12, 2010
Last Updated: July 2, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Columbia University:
Pancreatic Cancer
Pre-neoplastic lesions
Breast and Ovarian Cancer Syndrome
BRCA1/2
Mouse model for pancreatic cancer

Additional relevant MeSH terms:
Pancreatic Neoplasms
Carcinogenesis
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Neoplastic Processes
Pathologic Processes

ClinicalTrials.gov processed this record on September 18, 2014