Validation of a Mouse Model of Pancreatic Carcinogenesis

NCT ID: NCT01103128

Last Updated: 2015-06-23

Basic Information

• Recruitment Status: TERMINATED
• Total Enrollment: 450 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2009-03-31
• Study Completion Date: 2013-05-31

Brief 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.

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.

Conditions

Pancreatic Cancer

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: RETROSPECTIVE

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Columbia University

OTHER

Sponsor Role: lead

Responsible Party

Wendy K. Chung

Assistant Professor of Pediatrics, Molecular Genetics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Wendy K Chung, MD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

Locations

Columbia University Medical Center

New York, New York, United States

Countries

United States

Other Identifiers

AAAE0097

Identifier Type: OTHER

Identifier Source: secondary_id

AAAE0097

Identifier Type: -

Identifier Source: org_study_id