TY - JOUR T1 - Diverse tumour susceptibility in Collaborative Cross mice: identification of a new mouse model for human gastric tumourigenesis JF - Gut JO - Gut SP - 1942 LP - 1952 DO - 10.1136/gutjnl-2018-316691 VL - 68 IS - 11 AU - Pin Wang AU - Yunshan Wang AU - Sasha A Langley AU - Yan-Xia Zhou AU - Kuang-Yu Jen AU - Qi Sun AU - Colin Brislawn AU - Carolina M Rojas AU - Kimberly L Wahl AU - Ting Wang AU - Xiangshan Fan AU - Janet K Jansson AU - Susan E Celniker AU - Xiaoping Zou AU - David W Threadgill AU - Antoine M Snijders AU - Jian-Hua Mao Y1 - 2019/11/01 UR - http://gut.bmj.com/content/68/11/1942.abstract N2 - Objective The Collaborative Cross (CC) is a mouse population model with diverse and reproducible genetic backgrounds used to identify novel disease models and genes that contribute to human disease. Since spontaneous tumour susceptibility in CC mice remains unexplored, we assessed tumour incidence and spectrum.Design We monitored 293 mice from 18 CC strains for tumour development. Genetic association analysis and RNA sequencing were used to identify susceptibility loci and candidate genes. We analysed genomes of patients with gastric cancer to evaluate the relevance of genes identified in the CC mouse model and measured the expression levels of ISG15 by immunohistochemical staining using a gastric adenocarcinoma tissue microarray. Association of gene expression with overall survival (OS) was assessed by Kaplan-Meier analysis.Results CC mice displayed a wide range in the incidence and types of spontaneous tumours. More than 40% of CC036 mice developed gastric tumours within 1 year. Genetic association analysis identified Nfκb1 as a candidate susceptibility gene, while RNA sequencing analysis of non-tumour gastric tissues from CC036 mice showed significantly higher expression of inflammatory response genes. In human gastric cancers, the majority of human orthologues of the 166 mouse genes were preferentially altered by amplification or deletion and were significantly associated with OS. Higher expression of the CC036 inflammatory response gene signature is associated with poor OS. Finally, ISG15 protein is elevated in gastric adenocarcinomas and correlated with shortened patient OS.Conclusions CC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis. ER -