Abstract 3403: Telomere shortening in pancreatic cancer is correlated to KRAS mutation

Abstract

Abstract Background: Pancreatic cancer is characterized by genomic complexity and chromosomal instability, and atypical mitotic figures are morphological features of this phenotype. Previously we have reported that approximately 30% of total mitosis in pancreatic cancer was atypical including multipolar, lag-type, ring and asymmetrical mitosis, and anaphase bridges, and the number of total mitosis and atypical mitosis in pancreatic cancers was correlated with aggressive phenotype and prognosis (Pancreatology, 2016). In the present study, we clarified the relation between atypical mitotic figures, telomere length, and genetic abnormality in the pancreatic cancer. Methods: We surveyed the mitotic figures of the normal epithelium, pancreatic intraepithelial neoplasias (PanINs), and pancreatic cancers using surgically resected pancreatic cancer specimens (n=40). Telomere length was analyzed using quantitative fluorescent in situ hybridization technique. We also analyzed mutations of Kras codon 12 and 13 by PCR and microsatellite instability by immunohistochemical staining of MLH1, MSH2, MSH6 and PMS2. Results: Pancreatic cancer and duodenal epithelium showed significantly higher mitotic indices as compared with the duct, acinar cells, and PanINs. Normal mitosis was also higher in pancreatic cancers and the duodenal epithelium, while atypical mitosis was significantly elevated only in pancreatic cancers. Number of total mitosis and atypical mitosis were negatively correlated with telomere length, suggesting that telomere shortening plays important roles in cancer proliferation and chromosomal instability. In comparison with normal ducts, telomere length was decreased in PanIN-1, -2 and -3 and cancer. Furthermore, telomere length was gradually shorter among PanIN grades. Most of pancreatic cancers harbored mutations in Kras codon 12, and pancreatic cancer cases with Kras mutation showed shorter telomere length as compared with cases without Kras mutation. All pancreatic cancer cases in the present study were microsatellite stable. Conclusion: Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium plays key roles on carcinogenesis of the pancreas. Citation Format: Yoko Matsuda, Naotaka Izumiyama, Mutsunori Fujiwara, Naoshi Ishikawa, Junko Aida, Kaiyo Takubo, Toshiyuki Ishiwata, Tomio Arai. Telomere shortening in pancreatic cancer is correlated to KRAS mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3403. doi:10.1158/1538-7445.AM2017-3403