Data from Activation-Induced Cytidine Deaminase Contributes to Pancreatic Tumorigenesis by Inducing Tumor-Related Gene Mutations

Abstract

<div>Abstract<p>Pancreatic ductal adenocarcinoma (PDAC) develops via an accumulation of various gene mutations. The mechanism underlying the mutations in PDAC development, however, is not fully understood. Recent insight into the close association between the mutation pattern of various cancers and specific mutagens led us to investigate the possible involvement of activation-induced cytidine deaminase (AID), a DNA editing enzyme, in pancreatic tumorigenesis. Our immunohistochemical findings revealed AID protein expression in human acinar ductal metaplasia, pancreatic intraepithelial neoplasia, and PDAC. Both the amount and intensity of the AID protein expression increased with the progression from precancerous to cancerous lesions in human PDAC tissues. To further assess the significance of ectopic epithelial AID expression in pancreatic tumorigenesis, we analyzed the phenotype of <i>AID</i> transgenic (<i>AID</i> Tg) mice. Consistent with our hypothesis that AID is involved in the mechanism of the mutations underlying pancreatic tumorigenesis, we found precancerous lesions developing in the pancreas of <i>AID</i> Tg mice. Using deep sequencing, we also detected <i>Kras</i> and <i>c-Myc</i> mutations in our analysis of the whole pancreas of <i>AID</i> Tg mice. In addition, Sanger sequencing confirmed the presence of <i>Kras</i>, <i>c-Myc</i>, and <i>Smad4</i> mutations, with the typical mutational footprint of AID in precancerous lesions in <i>AID</i> Tg mice separated by laser capture microdissection. Taken together, our findings suggest that AID contributes to the development of pancreatic precancerous lesions by inducing tumor-related gene mutations. Our new mouse model without intentional manipulation of specific tumor-related genes provides a powerful system for analyzing the mutations involved in PDAC. <i>Cancer Res; 75(16); 3292–301. ©2015 AACR</i>.</p></div>