Abstract IA3: Genomic analysis reveals roles for chromatin modification and axon guidance in pancreatic cancer.

Abstract

Pancreatic cancer (PC) is the fourth leading cause of cancer death with an overall 5-year survival rate of < 5%, a statistic that has not changed in almost 50 years. A deeper understanding of the underlying molecular pathophysiology is expected to advance the urgent need to develop effective therapeutic and early detection strategies for this disease. Genomic characterization of pancreatic ductal adenocarcinoma (PDAC), which accounts for over 90% of PC has to date relied on targeted PCR-based exome sequencing of primary and metastatic lesions propagated as xenografts or cell lines. Here we use exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (Stage I and II) PDAC. Detailed analysis of 99 informative tumors identified 1,984 nonsilent mutations and 1,628 significant CNV events, and defined 439 significantly mutated genes based on stringent significant mutated gene and GISTIC analysis. Integration with functional data from in vitro shRNA and in vivo Sleeping Beauty-mediated somatic mutagenesis screens provided supportive evidence for 182 of these as candidate driver mutations. Pathway-based analysis recapitulated clustering of mutations in core signaling pathways in PDAC, and identified multiple new components in each, particularly in DNA damage repair mechanisms (ATM, TOP2A, RPA1, BRCC3). We also identified frequent and diverse somatic aberrations in genes involved in chromatin modification (SWI/SNF complex members, SETD2, EPC1), and novel mechanisms such as axon guidance (Semaphorin, Slit, Netrin and Ephrin signaling), extending the number of core perturbed pathways in PDAC. Aberrant expression of axon guidance genes co-segregated with poor patient survival and in animal models was associated with disease development and progression, further implicating perturbation of the axon guidance pathway as a novel mechanism important in PDAC. Citation Format: Andrew V. Biankin, John D. McPherson, Richard A. Gibbs, Australian Pancreatic Cancer Genome Initiative. Genomic analysis reveals roles for chromatin modification and axon guidance in pancreatic cancer. [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 IA3.