Diverse tumour susceptibility in Collaborative Cross mice: identification of a new mouse model for human gastric tumourigenesis

Abstract

ObjectiveThe 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.DesignWe 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.ResultsCC 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.ConclusionsCC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis.

Gut microbiome partially mediates and coordinates the effects of genetics on anxiety-like behavior in Collaborative Cross mice

“…The CC mouse model represents a genetically heterogeneous population with evenly distributed allele variation, and an allele frequency distribution similar to that of the human population 25 , 26 . This model has been used to study for example individual variation in motor performance 27 , gut microbiome composition 28 , cancer susceptibility 29 , memory performance 30 and viral pathogenesis 31 . This study provides new evidence for a complex interaction between host genetics, the gut microbiota and anxiety, and shows that the effect of genetics on anxiety can at least partially be mediated by the microbiome.…”

Collaborative Cross mice reveal extreme epilepsy phenotypes and genetic loci for seizure susceptibility

“…9 In addition, whole genome sequences have been generated for each individual CC strain, and other genomic tools have been developed to enable the identification of genetic variants from mapping studies. 9,10 The CC has been used to model complex traits such as behavior, [11][12][13] cancer, 14 and infectious disease susceptibility. 15 In order for us to take advantage of the immense genetic diversity available in the CC to study epilepsy, we needed a seizure induction protocol amenable to high throughput analysis.…”

High expression of TREM2 promotes EMT via the PI3K/AKT pathway in gastric cancer: bioinformatics analysis and experimental verification

“…In the past decade, the development of microarray technology and bioinformatics analyses tools has facilitated the discovery of some novel genes and pathways in the development of tumor from multiple levels as well as exploration of biomarkers related to tumor survival, prognosis, and diagnosis [3][4][5][6][7]. Many newly discovered genes have also been confirmed in cell and animal experiments [8,9].…”