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

Journal Article · · Gut
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [8];  [9];  [10];  [10];  [7];  [3];  [11];  [9];  [3];  [3]
  1. Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu (China). Dept. of Gastroenterology; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division; DOE/OSTI
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division; Second Hospital of Shandong University, Jinan (China). Clinical Laboratory
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division; Shandong Univ., Weihai (China). College of Marine Science
  5. Univ. of California Davis Medical Center, Sacramento, CA (United States). Dept. of Pathology
  6. Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing (China). Dept. of Pathology
  7. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Earth and Biological Sciences Directorate
  8. Texas A & M Univ., College Station, TX (United States). Dept. of Veterinary Pathobiology Texas A & M Univ., College Station, TX (United States). Dept. of Molecular and Cellular Medicine
  9. Texas A & M Univ., College Station, TX (United States). Dept. of Veterinary Pathobiology Texas A & M Univ., College Station, TX (United States). Dept. of Molecular and Cellular Medicine
  10. Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing (China). Dept. of Pathology
  11. Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu (China). Dept. of Gastroenterology
+ Show Author Affiliations
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.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1626189
Journal Information:
Gut, Journal Name: Gut Journal Issue: 11 Vol. 68; ISSN 0017-5749
Publisher:
BJMCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Gastroenterology & Hepatology