Marker development for the early detection of pancreatic cancer

KL Pogue-Geile PhD^a, RD George^a, JA Mackey^a, KKW Lee^b, AJ Moser^b, D Crispin^c, T Brentnall^c, DC Whitcomb^a

^aDepartment of Medicine, ^bDepartment of Surgery; University of Pittsburgh, Pittsburgh, PA, Seattle, ^cDepartment of Medicine, University of Washington, Washington, WA, Seattle

AIM: The purpose of the following work is to identify markers that will allow for the early detection of pancreatic cancer. Methods: We have developed the Pittsburgh Pancreas gene-Enriched ARray – PittPEAR- which is composed of 5,763 pancreas and pancreatic cancer expressed genes. We have compared gene expression in pancreatic adenocarcinoma to the normal pancreas (donor normal) and identified those genes that are the most significantly differentially expressed in pancreatic cancer. However, a major problem in determining what gene expression changes occur EARLY in pancreatic cancer is the acquisition of early pancreatic cancer material. There is no recognized preneoplastic histological feature in pancreatic cancer that is similar to the polyp in colon cancer. Therefore, we have used two different sources of preneoplastic tissues. One is a pancreas tissue sample with PanINIII lesions. This tissue would have almost certainly developed pancreatic cancer because it was taken from a patient whose family exhibited an autosomal dominant inheritance pattern of pancreatic cancer (Family X-Eberle et al, Am J of Human Genetics 70:1044-48,2002). We also profiled gene expression changes in pancreatic normal adjacent tissue (histologically normal tissue adjacent to cancer) to determine whether normal adjacent tissue exhibited gene expression changes indicative of cancer. The expression patterns of these preneoplastic tissues were compared to donor normal pancreas. Results: We have generated lists of the most significantly differentially expressed genes from each data set (pancreatic adenocarcinoma, PanINIII-Family X and normal adjacent) using a web based tool developed by Jim Lyons-Weiler, Ph.D. at the University of Pittsburgh. The most similarity was found between the normal adjacent tissue and the pancreatic cancers. At least 50% of the genes that show the greatest differential expression are identical in both the cancer and the normal adjacent lists although the rank ordering of significance varies somewhat between the two lists. Genes under expressed on both the cancer and normal adjacent list include regenerating islet-derived 1 alpha, period (Drosophilia) homolog 1, RNA binding motif, single stranded interacting protein, an EST similar to pancreatitis associated protein and eukaryotic translation elongation factor 2. When we expanded our comparisons to the PanIN III tissue from Family X, we found a subset of genes that were significantly over expressed in all 3 data sets, including ribosomal protein S27a, nucleolin, villin 1 and KIAA 1705. Conclusions: Normal adjacent tissue appears to contain many gene expression changes indicative of the neighboring cancer, indicating that normal adjacent cancer is NOT normal. Some of these same changes occur early in preneoplastic tissues. Genes with the same significant pattern of differential expression in cancer, and in preneoplastic tissues such as normal adjacent and in PanINIII tissues represent possible biomarkers for pancreatic cancer.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in poster session 892 (Susceptibility genes).