P7009 Precancerous molecular features committing development of colonic polyps revealed by studies on the porcine model of human familial adenomatous polyposis. (1st September 2016)

• Record Type: Journal Article
• Authors: Flisikowska, T.; Wander, C.; Wagner, A.; Bruening, F.; Kind, A.; Flisikowski, K.; Schnieke, A.; Wurmser, C.; Fries, R.; Stachowiak, M.; Perkowska, A.; Switonski, M.; Bauersachs, S.; Saur, D.
• Is Part Of: Journal of animal science. Volume 94(2016)Supplement 4
• Page Start: 179
• Page End: 180
• Publication Date: 2016-09-01
• Subjects: colorectal cancer -- APC -- swine; Livestock -- Periodicals; Livestock; Electronic journals; Periodicals; 636.005
• DOI: 10.2527/jas2016.94supplement4179b
• Languages: English
• ISSNs: 0021-8812

Abstract

Abstract: Colorectal cancer (CRC) has variable clinical behavior, with only a small proportion of colon polyps progressing to cancer. Molecular classification of polyps could improve the discrimination of those polyps destined to become cancerous from those that are not, and thus aid strategies for early CRC therapy. Using our familial adenomatous polyposis (FAP) pig model based on the APC 1311 mutation, we attempted to identify molecular features associated with early transformation and the severity of colon polyposis. Four generations of APC 1311/+ pigs were produced and examined by regular endoscopic examination. We performed global gene and miRNA expression analyses on biopsied samples of normal colonic mucosa, and low- (LG-IEN) and high-grade (HG-IEN) intraepithelial neoplastic polyps. We also measured the expression of selected miRNAs in the general blood circulation. These data were integrated and analyzed for association with clinical data. As in humans, a single heterozygous APC 1311 mutation resulted in polyps in the large intestine. Analysis of our pig herd revealed that genetic background influences the severity of polyposis, resulting in some full siblings with markedly different numbers of polyps. The transformation of polyps was rapid, with some young pigs showing HG-IEN. Unsupervised clustering of RNA-sequencing data revealed transcriptome changes associated with early polyp development, including molecular pathways involved in metabolic processes and immune response. We also observed that the severity of polyposis is associated with differential expression of miRNAs in normal mucosa and may be estimated using the expression profiles of circulating miRNAs. Our study identified molecular features involved in cancerous early polyp transformation that might be used for transcriptome-based classification. This work was supported by the following grants: National Science Centre in Poland, Grant No. 2013/10/M/NZ2/00284, and Mildred Scheel Stiftung für Krebsforschung in Germany. The authors are members of COST Action BM1308 'Sharing Advances on Large Animal Models' (SALAAM).