Abstract B9: Metastasis-associated loci in pancreatic cancer identified using Sleeping Beauty insertional mutagenesis.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fifth most common cancer in the U.S. and highly metastatic. Recent sequencing efforts in human pancreatic cancer have investigated the clonal relationships between primary tumors and derived metastatic lesions. We have conducted a mutagenic screen using Sleeping Beauty (SB) in an oncogenic Kras pancreatic cancer mouse model to identify new candidate cancer genes. We recently published the characterization of loci commonly mutated in primary pancreatic tumors (Mann et al. Proc Natl Acad Sci U S A. 2012 Mar 15). Importantly, we showed that SB drives invasive, highly metastatic pancreatic adenocarcinoma with multiple metastases to the liver, lung, duodenum and lymph nodes, sites commonly involved in the human disease. In an effort to understand the clonal evolution of these metastatic events with respect to the primary tumor, we sequenced the SB insertion tags from 16 metastases originating from 11 animals. Using two independent statistical methods, we identified 78 commonly mutated loci in the metastatic lesions. Interestingly, half of these loci are found only in metastases. The majority of the loci commonly mutated in the primary tumors are not mutated in the metastases, suggesting that the seeding subclones of the metastases disseminated early during the development of the tumor. The metastatic subclones acquired additional SB insertions that were maintained through positive selection. The primary sequencing data also suggest ongoing clonal evolution of the primary tumors from which the metastases arose. Human PDAC sequencing data also support this observation. SB-driven metastases are enriched in mutations in genes involved in Wnt signaling and arrest in the G1 phase of the cell cycle. Efforts to investigate the biological impact of these mutations on metastasis in PDAC are ongoing. Future studies will involve laser capture microdissection of primary tumors and metastases to refine the relationship between primary subclones and metastatic lesions.

Citation Format: Karen M. Mann, Nancy A. Jenkins, Neal G. Copeland. Metastasis-associated loci in pancreatic cancer identified using Sleeping Beauty insertional mutagenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B9.