Author:
Araki Tomoyuki,Miwa Naofumi
Abstract
Abstract
Objective
Pancreatic cancer (PC) originates and progresses with genetic mutations in various oncogenes and suppressor genes, notably KRAS, CDKN2A, TP53, and SMAD4, prevalent across diverse PC cells. In addition to genetic mutations/deletions, persistent exposure to high-risk factors, including obesity, induces whole-genome scale epigenetic alterations contributing to malignancy. However, the impact of obesity on DNA methylation in the presymptomatic stage, particularly in genes prone to PC mutation, remains uncharacterized.
Results
We analyzed the methylation levels of 197 loci in six genes (KRAS, CDKN2A, TP53, SMAD4, GNAS and RNF43) using Illumina Mouse Methylation BeadChip array (280 K) data from pancreatic exocrine cells obtained from high-fat-diet (HFD) induced obese mice. Results revealed no significant differences in methylation levels in loci between HFD- and normal-fat-diet (NFD)-fed mice, except for RNF43, a negative regulator of Wnt signaling, which showed hypermethylation in three loci. These findings indicate that, in mouse pancreatic exocrine cells, high-fat dietary obesity induced aberrant DNA methylation in RNF43 but not in other frequently mutated PC-related genes.
Publisher
Springer Science and Business Media LLC
Reference30 articles.
1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
2. Chakraborty S, Baine MJ, Sasson AR, Batra SK. Current status of molecular markers for early detection of sporadic pancreatic cancer. Biochim Biophys Acta. 2011;1815:44–64.
3. Momi N, Kaur S, Krishn SR, Batra SK. Discovering the route from inflammation to pancreatic cancer. Minerva Gastroenterol Dietol. 2012;58:283–97.
4. Smit VT, Boot AJ, Smits AM, et al. KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res. 1988;16:7773–82.
5. Caldas C, Hahn SA, de Costa LT, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet. 1994;8(1):27–32.