Abstract B89: Identification of dysregulated pathways in pancreatic cancer through gene set and subnetwork enrichment analyses of transcriptome and DNA methylome data.

Abstract

Pancreatic cancer is the fourth leading cause of cancer deaths in the U.S., and its mortality rate is nearly equal to the rate of incidence. This is due largely to poor diagnostic markers and a lack of viable therapeutic options. In an effort to better understand the underlying genetic dysregulation of this complex and insidious disease, we compared whole-genome expression and DNA methylation profiles in tumor versus normal pancreatic samples by mRNA-sequencing and microarray analysis of methyl-DNA immunoprecipitations (MeDIP-chip), respectively. Our results indicate 4,139 genes are significantly differentially expressed (DE), and of those genes 746 are putatively regulated by differential DNA methylation (DM). Pathway analyses of DE genes reveal enrichment in GO Biological Processes related to stress response, cell adhesion and tissue development, as well as enrichment in annotated gene sets for diseases like pancreatitis and various gastrointestinal neoplasms, including pancreatic neoplasms. Regulatory subnetwork enrichment analyses of the DE results indicate significant enrichment in expression subnetworks regulated by important factors in pancreatic development, pancreatitis and diabetes. The top two expression subnetworks are regulated by HNF1A and HNF4A, which form a cross-regulatory loop with each other. Mutations in HNF1A and HNF4A cause maturity onset diabetes of the young (MODY) type 3 and 1, respectively. HNF1A was also recently shown to be important for exocrine pancreas homeostasis and regeneration after induced acute pancreatitis. This suggests a possible role for HNF1A in the poorly understood epidemiological associations between pancreatic cancer and both diabetes and pancreatitis. Citation Format: Jason Hoskins, Jinping Jia, Hemang Parikh, Irene Collins, Snorri Thorgeirsson, Ken Lo, Perwez Hussain, Gloria Petersen, Laufey Amundadottir. Identification of dysregulated pathways in pancreatic cancer through gene set and subnetwork enrichment analyses of transcriptome and DNA methylome data. [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 B89.